Diamino-Pyridine, Pyrimidine, and Pyridazine Modulators of the Histamine H4 Receptor

ABSTRACT

Diamino-pyridine, pyrimidine and pyridazine compounds which may be used as H 4  receptor modulators, and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H 4  receptor activity, such as allergy, asthma, autoimmune diseases, and pruritis.

FIELD OF THE INVENTION

The present invention relates to certain diamino-pyridine, pyrimidine,and pyridazine compounds, pharmaceutical compositions containing them,methods of making them, and methods of using them for the modulation ofthe histamine H₄ receptor and for the treatment of disease states,disorders, and conditions mediated by histamine H₄ receptor activity.

BACKGROUND OF THE INVENTION

The histamine H₄ receptor (H₄R), sometimes also referred to simply as“H4” or “H₄”, is the most recently identified receptor for histamine(for reviews, see: Fung-Leung, W.-P., et al., Curr. Opin. Invest. Drugs2004, 5(11), 1174-1183; de Esch, I. J. P., et al., Trends Pharmacol.Sci. 2005, 26(9), 462-469; Zhang, M. et al. Pharmacol. Ther. 2007, 113,594-606; Thurmond, R. L. et al. Nat. Rev. Drug Disc. 2008, 7, 41-53;Zhang, M. et al. Expert Opin. Investig. Drugs 2006, 15(11), 1443-1452).The receptor is found in the bone marrow and spleen and is expressed oneosinophils, basophils, mast cells (Liu, C., et al., Mol. Pharmacol.2001, 59(3), 420-426; Morse, K. L., et al., J. Pharmacol. Exp. Ther.2001, 296(3), 1058-1066; Hofstra, C. L., et al., J. Pharmacol. Exp.Ther. 2003, 305(3), 1212-1221; Lippert, U., et al., J. Invest. Dermatol.2004, 123(1), 116-123; Voehringer, D., et al., Immunity 2004, 20(3),267-277), CD8⁺T cells (Gantner, F., et al., J. Pharmacol. Exp. Ther.2002, 303(1), 300-307), dendritic cells, and human synovial cells fromrheumatoid arthritis patients (Ikawa, Y., et al., Biol. Pharm. Bull.2005, 28(10), 2016-2018). The histamine H₄ receptor is also elevated inhuman nasal polyp tissue (Jókúti, A. et al. Cell. Biol. Int. 2007, 31,1367-1370). However, expression in neutrophils and monocytes is lesswell defined (Ling, P., et al., Br. J. Pharmacol. 2004, 142(1), 161-171;Damaj, B. B. et al. J. Immunol. 2007, 179, 7907-7915). Receptorexpression is at least in part controlled by various inflammatorystimuli (Coge, F., et al., Biochem. Biophys. Res. Commun. 2001, 284(2),301-309; Morse, et al., 2001), thus supporting that H₄ receptoractivation influences inflammatory responses. Because of itspreferential expression on immunocompetent cells, the H₄ receptor isclosely related with the regulatory functions of histamine during theimmune response.

A biological activity of histamine in the context of immunology andautoimmune diseases is closely related with the allergic response andits deleterious effects, such as inflammation. Events that elicit theinflammatory response include physical stimulation (including trauma),chemical stimulation, infection, and invasion by a foreign body. Theinflammatory response is characterized by pain, increased temperature,redness, swelling, reduced function, or a combination of these.

Mast cell degranulation (exocytosis) releases histamine and leads to aninflammatory response that may be initially characterized by ahistamine-modulated wheal and flare reaction. A wide variety ofimmunological stimuli (e.g., allergens or antibodies) andnon-immunological (e.g., chemical) stimuli may cause the activation,recruitment, and de-granulation of mast cells. Mast cell activationinitiates allergic inflammatory responses, which in turn cause therecruitment of other effector cells that further contribute to theinflammatory response. It has been shown that histamine induceschemotaxis of mouse mast cells (Hofstra, et al., 2003). Chemotaxis doesnot occur using mast cells derived from H₄ receptor knockout mice.Furthermore, the response is blocked by an H₄-specific antagonist, butnot by H₁, H₂ or H₃ receptor antagonists (Hofstra, et al., 2003;Thurmond, R. L., et al., J. Pharmacol. Exp. Ther. 2004, 309(1),404-413). The in vivo migration of mast cells to histamine has also beeninvestigated and shown to be H₄ receptor dependent (Thurmond, et al.,2004). The migration of mast cells may play a role in allergic rhinitisand allergy where increases in mast cell number are found (Kirby, J. G.,et al., Am. Rev. Respir. Dis. 1987, 136(2), 379-383; Crimi, E., et al.,Am. Rev. Respir. Dis. 1991, 144(6), 1282-1286; Amin, K., et al., Am. J.Resp. Crit. Care Med. 2000, 162(6), 2295-2301; Gauvreau, G. M., et al.,Am. J. Resp. Crit. Care Med. 2000, 161(5), 1473-1478; Kassel, O., etal., Clin. Exp. Allergy 2001, 31(9), 1432-1440). In addition, it isknown that in response to allergens there is a redistribution of mastcells to the epithelial lining of the nasal mucosa (Fokkens, W. J., etal., Clin. Exp. Allergy 1992, 22(7), 701-710; Slater, A., et al., J.Laryngol. Otol. 1996, 110, 929-933). These results show that thechemotactic response of mast cells to histamine is mediated by histamineH₄ receptors.

It has been shown that eosinophils can chemotax towards histamine(O′Reilly, M., et al., J. Recept. Signal Transduction 2002, 22(1-4),431-448; Buckland, K. F., et al., Br. J. Pharmacol. 2003, 140(6),1117-1127; Ling et al., 2004). Using H₄ selective ligands, it has beenshown that histamine-induced chemotaxis of eosinophils is mediatedthrough the H₄ receptor (Buckland, et al., 2003; Ling et al., 2004).Cell surface expression of adhesion molecules CD11b/CD18 (LFA-1) andCD54 (ICAM-1) on eosinophils increases after histamine treatment (Ling,et al., 2004). This increase is blocked by H₄ receptor antagonists butnot by H₁, H₂, or H₃ receptor antagonists.

The H₄R also plays a role in dendritic cells and T cells. In humanmonocyte-derived dendritic cells, H₄R stimulation suppresses IL-12p70production and drives histamine-mediated chemotaxis (Gutzmer, R., etal., J. Immunol. 2005, 174(9), 5224-5232). A role for the H₄ receptor inCD8⁺ T cells has also been reported. Gantner, et al., (2002) showed thatboth H₄ and H₂ receptors control histamine-induced IL-16 release fromhuman CD8⁺ T cells. IL-16 is found in the bronchoalveolar fluid ofallergen- or histamine-challenged asthmatics (Mashikian, V. M., et al.,J. Allergy Clin. Immunol. 1998, 101 (6, Part 1), 786-792; Krug, N., etal., Am. J. Resp. Crit. Care Med. 2000, 162(1), 105-111) and isconsidered important in CD4⁺ cell migration. The activity of thereceptor in these cell types indicates an important role in adaptiveimmune responses such as those active in autoimmune diseases.

In vivo H₄ receptor antagonists were able to block neutrophillia inzymosan-induced peritonitis or pleurisy models (Takeshita, K., et al.,J. Pharmacol. Exp. Ther. 2003, 307(3), 1072-1078; Thurmond, et al.,2004). In addition, H₄ receptor antagonists have activity in a widelyused and well-characterized model of colitis (Varga, C., et al., Eur. J.Pharmacol. 2005, 522(1-3), 130-138). These results support theconclusion that H₄ receptor antagonists have the capacity to beanti-inflammatory in vivo.

Another physiological role of histamine is as a mediator of itch and H₁receptor antagonists are not completely effective in the clinic.Recently, the H₄ receptor has also been implicated in histamine-inducedscratching in mice (Bell, J. K., et al., Br. J. Pharmacol. 2004, 142(2),374-380). The effects of histamine could be blocked by H₄ antagonists.These results support the hypothesis that the H₄ receptor is involved inhistamine-induced itch and that H₄ receptor antagonists will thereforehave positive effects in treating pruritis. Histamine H₄ receptorantagonists have been shown to attenuate experimental pruritis (Dunford,P. J. et al. J. Allergy Clin. Immunol. 2007, 119(1), 176-183).

Modulation of H₄ receptors controls the release of inflammatorymediators and inhibits leukocyte recruitment, thus providing the abilityto prevent and/or treat H₄-mediated diseases and conditions, includingthe deleterious effects of allergic responses such as inflammation.Compounds according to the present invention have H₄ receptor modulatingproperties. Compounds according to the present invention have leukocyterecruitment inhibiting properties. Compounds according to the presentinvention have anti-inflammatory properties. Modulation of the histamineH₄ receptor has also been implicated in the treatment of pain (Intl.Pat. Appl. Publ. WO 2008/060766 (Abbott).

Numerous pro-inflammatory cytokines have been increasingly reported tobe elevated in patients suffering of major depression (Frommberger etal.,

European Archives of Psychiatry & Clinical Neuroscience. 1997, 247(4),228-33; Sluzewska A., et al., Psychiatry Research, 1996, 64(3), 161-7;Ortiz-Dominguez, et al., Bip. Disporder 9, 2007; O′Brien, et al., J.Affective Disorders, 2006, 90, 263-267; Anisman H. et al., BiologicalPsychiatry, 1999, 46(12),1649-55)(when compared with non-depressedsubjects or, in some cases, correlated with symptom severity). Theseinclude increased acute-phase proteins (Kling et al., Biol. Phychiatry,2007, 62, 309-313; Kim et al., Progress in Neuro-Psychopharmacology &Biological Psychiatry, 2007, 31, 1044-1053; (C-reactive protein,a-1-acid glycoprotein, a-1-antichymotrypsin and haptoglobin), increasedexpression of chemokines and adhesion molecules (including humanmacrophage chemoattractant protein-1 (MCP-1), soluble intracellularadhesion molecule-1 (sICAM-1) and E-selectin), increased serum and/orplasma concentrations of interleukin (Il)-1-β, IL-6, and tumor necrosisfactor (TNF)-α, both in the peripheral blood circulation and in thecentral nervous system (particularly in the cerebrospinal fluid) with ahigher level of consistency when measuring TNF-α and IL-6 (O′Brien etal., Journal of Psychiatric Research, 2007, 41, 326-331; Moorman et al.,J. of Cardiac Failure, 2007, 13(9), 738-43; Soygur et al., Progress inNeuro-Psychopharmacology & Biolofical Psychiatry, 2007, 31, 1242-1247).Additionally, allelic variants of the genes for IL-1β and TNF-α increasethe risk for depression and are associated with reduced responsivenessto antidepressant therapy. Finally, there is available preclinicalevidence supporting the involvement of several cytokines in models ofdepression and some clinical evidence of the involvement of cytokinesantagonism in the treatment of depressive symptoms on patients sufferingfrom active inflammatory diseases (Kim et al., Progress inNeuro-Psychopharmacology & Biological Psychiatry, 2007, 31, 1044-1053).

[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[341-methyl-piperidin-4-ylypropyl]-amine(U.S. Pat. No. 7,507,737, Example 2) is a potent antagonist of the H₄receptor (H₄R) with a K_(i) of 8.4 nM and greater than 25-foldselectivity over other histamine receptors in vitro. It inhibitedhistamine-induced shape change of eosinophils, chemotaxis of mast cells,and IL-6 production in mast cells. In vivo,[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-aminereduced inflammation in mouse models of asthma, arthritis anddermatitis. The compound also inhibited lipopolysaccharide (LPS)-inducedtumor necrosis factor alpha (TNF-α) production and other cytokines invivo.

Based on this the evidence and the effects of H₄R antagonism it isproposed that[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3(1-methyl-piperidin-4-yl)-propyl]-amineand its chemically related family of compounds has antidepressant and/oranxiolytic properties suitable for the treatment of mood disorders(including but not limited to Major Depressive Disorder, BipolarDisorder, Treatment Resistant Major Depressive Disorder and TreatmentResistant Bipolar Disorder), anxiety disorders (including but notlimited to Generalized Anxiety Disorder, Social Phobia, and posttraumatic stress disorder). It is envisaged that H₄ antagonists willshare such properties suitable for the treatment of such disorders.

Adiposity-associated inflammation and insulin resistance are associatedwith the development of type II diabetes, fatty liver andatherosclerosis. Macrophages are recruited into adipose tissue andatherosclerotic plaques, and are activated to release inflammatorycytokines and chemokines. High fat diets associated with the developmentof these conditions may lead to increased gut permeability anddyslipidemia. Consequent toll-ligand receptor, 2 and 4 (TLR2, TLR4)activation of adipocytes and macrophages by bacteria and by high levelsof free fatty acids leads to an inflammatory phenotype and insulinresistance. Specifically, insulin signaling pathways may be attenuatedby cytokines such as TNFα and IL-6 and activation of kinases includingc-jun kinase, NKkB or PKCθ, downstream of TLR2/4 stimulation. Effects oninsulin receptor signaling are potentiated by increased infiltration ofmonocyte/macrophages into the tissue by release of chemokines such asMCP-1.

H4R is a high affinity receptor for histamine expressed onmonocyte/macrophage populations and other hematopoietic cells.Antagonism of the H4R has been shown to reduce TLR4 signaling in vitroand to reduce TLR2 and TLR4 mediated inflammatory cytokine production invitro and in vivo. Levels of pro-inflammatory mediators including TNF-α,IL-6 and LTB4 have been variously shown to be inhibited by H4Rantagonism in TLR dependent systems. Data obtained in the context ofthis invention support the claim that H4R antagonists have beneficialproperties towards the treatment of type 2 diabetes and relatedmetabolic disorders through inflammation reduction.

Histamine H₄ receptor antagonists have anti-inflammatory andanti-pruritic activity in animal models when given systemically. Thisinvention also relates to the use of topical formulations of H₄ receptorantagonists for the topical treatment of dermal inflammation andpruritus. The use of topical therapies for skin conditions such asurticaria and atopic dermatitis may be preferred over systemicadministration due to improved safety profiles. The topical applicationof an H₄ receptor antagonist,(5-chloro-1H-indo1-2-yl)-(4-methyl-piperazin-1-yl)-methanone (U.S. Pat.No. 6,803,362, Example 1) was tested in the context of this invention ina mouse model of pruritus. The results support the claim that topicaltreatment with H₄ receptor antagonists have beneficial propertiestowards topical anti-pruritic treatment, and it is envisaged that theyalso have such properties regarding topical anti-inflammatory treatment.Topical formulation of such antagonists may have utility in both humanand veterinary health.

Examples of textbooks on the subject of inflammation include: 1) Gallin,J. I.; Snyderman, R., Inflammation: Basic Principles and ClinicalCorrelates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999;2) Stvrtinova, V., et al., Inflammation and Fever. PathophysiologyPrinciples of Diseases (Textbook for Medical Students); Academic Press:New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W. B.Saunders Co., 1988; and 4) Stedman's Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following:Nathan, C., Nature 2002, 420(6917), 846-852; Tracey, K. J., Nature 2002,420(6917), 853-859; Coussens, L. M., et al., Nature 2002, 420(6917),860-867; Libby, P., Nature 2002, 420, 868-874; Benoist, C., et al.,Nature 2002, 420(6917), 875-878; Weiner, H. L., et al., Nature 2002,420(6917), 879-884; Cohen, J., Nature 2002, 420(6917), 885-891;Steinberg, D., Nature Med. 2002, 8(11), 1211-1217.

Thus, small-molecule histamine H₄ receptor modulators according to thisinvention control the release of inflammatory mediators and inhibitleukocyte recruitment, and may be useful in treating inflammation ofvarious etiologies, including the following conditions and diseases:inflammatory disorders, allergic disorders, dermatological disorders,autoimmune disease, lymphatic disorders, pruritis, and immunodeficiencydisorders. Diseases, disorders and medical conditions that are mediatedby histamine H₄ receptor activity include those referred to herein.

Certain diamine-substituted pyridines are described in the followingpublications: Intl. Pat. Appl. Publ. WO 2008/122378 (UCB Pharma, Oct.16, 2008); Intl. Pat. Appl. Publ. WO 1991/09849 (Upjohn, Jul. 11, 1991);Intl. Pat. Appl. Publ. WO 2006/063718 (Hoffmann La Roche, Jun. 22,2006); U.S. Pat. No. 4,788,196 (Pfizer, Nov. 29, 1988); and U.S. Pat.No. 4,806,536 (Pfizer, Feb. 21, 1989).

Certain amine-substituted 2-aminopyrimidines are disclosed in thefollowing publications: Becker, I. J. Het. Chem. 2005, 42(7), 1289-1295;Eur. Pat. Appl. No. EP 1437348 (Jul. 14, 2004); U.S. Pat. No. 3,907,801(Sep. 23, 1975); Lespagnol, A. et al. Chim. Therap. 1971, 6(2), 105-108;Willecomme, B. Annales de Chimie 1969, 4(6), 405-428; Lespagnol, A. etal. Chim. Therap. 1965, 1, 26-31; Intl. Pat. Appl. Publ. WO 2001/62233(Aug. 30, 2007); Intl. Pat. Appl. Publ. WO 2001/47921 (Jul. 5, 2001);U.S. Pat. Appl. Publ. US 2007/0167459 (Ono Pharmaceutical Co., Jul. 19,2007); U.S. Pat. Appl. Publ. US 2003/0105106 (Pfizer, Jun. 5, 2003);U.S. Pat. Appl. Publ. US 2002/0147200 (Nilsson, Oct. 10, 2002); and U.S.Pat. No. 5,147,876 (Mitsui, Sep. 15, 1992).

Certain amine-substituted 2-aminopyridazines are disclosed in thefollowing publications: Heinisch, G. Heterocycles 1999, 51(5),1035-1050; U.S. Pat. Appl. Publ. US 2005182067 (Amgen Inc., Aug. 18,2005) and Intl. Pat. Appl. WO 2002/022605 (Vertex Pharmaceuticals Inc.,March 21, 2002). Additionally,(5-piperazin-1-yl-pyridazin-3-yl)-p-tolyl-amine (CAS No. 1092336-93-0)is commercially available.

Certain substituted 2-aminopyrimidines as histamine H₄ antagonists aredisclosed in Intl. Pat. Appl. Publ. WO 2008/074445 (UCB Pharma, Jun. 26,2008); WO 2005/054239 (Bayer Healthcare AG; Jun. 16, 2005) and EP1505064 (Bayer Healthcare AG; Feb. 9, 2005; counterpart of Intl. Pat.Appl. Publ. WO 2005/014556). Substituted pyrimidines are described ashistamine H₄ ligands in U.S. Pat. Appl. Publ. 2007/0185075 (PharmaciaCorp.; Aug. 9, 2007), Intl. Pat. Appl. Publ. WO 2007/031529 (PalauPharma S.A.; Mar. 22, 2007), and U.S. pat. appl. Ser. No. 12/070,051(Feb. 14, 2008). Additional disclosures of amino pyrimidines ashistamine H₄ ligands include: Intl. Pat. Appl. Publ. Nos. WO2007/090852, WO 2007/090853, and WO 2007/090854 (Aug. 16, 2007), and EP1767537 (Mar. 28, 2007), all reported by Cellzome Ltd., Intl. Pat. Appl.Publ. Nos. WO 2008/031556 (UCB Pharma; Mar. 20, 2008), WO 2006/050965(Argenta; May 18, 2006), and WO 2007/072163 (Pfizer; Jun. 28, 2007).

However, there remains a need for potent histamine H₄ receptormodulators with desirable pharmaceutical properties. Certaindiamino-pyridine, pyrimidine and pyridazine derivatives have been foundin the context of this invention to have histamine H₄receptor-modulating activity.

SUMMARY OF THE INVENTION

One aspect of this invention concerns compounds of Formula (I)

wherein

Z is CH or N;

Y is CH or N;

Z and Y are defined independently of each other, and the ring containingsaid

Y and Z members does not have more than two nitrogen members; providedthat

i) when Y is CH and Z is CH or N, then;

R¹ is:

a) —(CH₂)₂OCH₃, —(CH₂)₂SCH₃, or C₁₋₈alkyl, each independentlyunsubstituted or substituted with —OH or —CF₃;

b) —(CH₂)₀₋₂—Ar¹, —CHR²—Ar¹, or —(CH₂)₀₋₂—Ar², each of said Ar¹ and Ar²independently unsubstituted or substituted with halo, —CH₃, or —OCH₃,

Ar¹ is a 6-membered aromatic carbocyclic ring,

Ar² is a 5 to 6-membered heteroaromatic ring containing N, S or O; or

c) cycloalkyl, —(CH₂)-(monocyclic cycloalkyl), —(CH₂)-(bridgedpolycyclic cycloalkyl)₀₋₁, —(CHR²)-(monocyclic cycloalkyl),—(CH₂)-(fused cycloalkyl), —(CH₂)-(bridged monocyclic cycloalkyl),—(CH₂)₀₋₁-tetrahydrofuranyl, or —(CH₂)₀₋₁-tetrahydropyranyl, each ofsaid cycloalkyl independently unsubstituted or substituted with one,two, or three C₁-₄alkyl substituents;

R² is —C₁₋₄alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃alkyl;provided that:

when R¹ is isopropyl, then R^(c) is methyl;

when R¹ is 4-methylphenyl, then R^(c) is methyl;

when Z is N, Y is CH, and R¹ is benzyl unsubstituted or substituted withhalo, then R^(c) is methyl;

ii) when Y is N and Z is CH, then;

R¹ is:

-   -   a) —(CH₂)₂OCH₃, —(CH₂)₂SCH₃, or C₁₋₈alkyl, each independently        unsubstituted or substituted with —OH or —CF₃;    -   b) —(CH₂)₀₋₂—Ar¹, —CH₂)₀₋₂—Ar², each of said Ar¹ and Ar²        independently unsubstituted or substituted with halo, —CH₃,        —OCH₃,    -   Ar¹ is a 6-membered aromatic carbocyclic ring,    -   Ar² is a 5 to 6-membered heteroaromatic ring containing N, S or        O; or    -   c) cycloalkyl, —(CH₂)-(monocyclic cycloalkyl), —(CH₂)-(bridged        polycyclic cycloalkyl)₀₋₁, —(CHR²)-(monocyclic cycloalkyl),        —(CH₂)-(fused cycloalkyl), —(CH₂)-(bridged monocyclic        cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl,        —(CH₂)₀₋₁-tetrahydropyranyl, each independently unsubstituted or        substituted with one, two, or three C₁₋₄alkyl substituents;

R² is —C₁₋₄alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃alkyl.

Other embodiments concern chemical entities of Formula (I) where Y isCH, and Z is CH or N.

Further embodiments concern chemical entities of Formula (I) where Y isN and Z is CH.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to pharmaceuticalcompositions for treating a disease, disorder, or medical conditionmediated by histamine H₄ receptor activity, comprising an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of Formula (I).

Pharmaceutical compositions according to the invention may furthercomprise a pharmaceutically acceptable excipient.

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by histamine H₄ receptor activity, comprisingadministering to the subject in need of such treatment an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is inflammation. Inflammation hereinrefers to the response that develops as a consequence of histaminerelease, which in turn is caused by at least one stimulus. Examples ofsuch stimuli are immunological stimuli and non-immunological stimuli.

In another aspect, the chemical embodiments of the present invention areuseful as histamine H₄ receptor modulators. Thus, the invention isdirected to a method for modulating histamine H₄ receptor activity,including when such receptor is in a subject, comprising exposinghistamine H₄ receptor to an effective amount of at least one chemicalentity selected from compounds of Formula (I), pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of compounds of Formula (I).

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS

The disclosures of the publications, including but not limited topatents and patent applications, cited anywhere in any part of thisspecification are incorporated herein by reference in their entirety.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 12ring atoms per carbocycle. Where the term cycloalkyl is qualified by aspecific characterization, such as monocyclic, fused polycyclic, bridgedpolycyclic, and spiro polycyclic, then such term cycloalkyl refers onlyto the carbocycle so characterized. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to refer also to anyone of hydrates, solvates, and polymorphs of such compounds, andmixtures thereof, even if such forms are not listed explicitly. In someembodiments, the solvent is water and the solvates are hydrates.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH(_(s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH(_(s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH(_(aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ ^(and) S² _(example)is S₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹example is S2 andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology _(“S) ¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(a-c), and Z, and any other generic substituent symbol usedherein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(a-c), and Z, and any other generic substituent symbol usedherein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent —A—B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Some embodiments are given by compounds of Formula (I) where Y is CH, Zis CH or N, and R¹ is C₁₋₈alkyl (unsubstituted or substituted with —OHor —CF₃), phenyl, pyridyl, benzyl, pyridin-2-ylmethyl, phenylethyl,1-phenyl-ethyl (each independently unsubstituted or substituted withhalo, —CH₃, —OCH₃), cycloalkyl, —(CH₂)-(monocyclic cycloalkyl),—(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH₂)-(bridged polycyclic cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl (each independently unsubstituted orsubstituted with one, two, or three C₁₋₄alkyl substituents). In some ofthese embodiments, R¹ is

2,2-dimethylpropanol, 2,2-dimethylpropan-1-ol, 2,2-dimethylpropyl,2-methyl-1-propan-2-ol, 2-methylpropan-2-ol, 3-propanol,(1-methylethyl), 2,2-dimethylpropyl, 2-methoxyethyl, 2-methylpropyl,4,4,4-trifluorobutyl, propyl, butyl, tert-butyl, propan-1-ol,2-(methylsulfanyl)ethyl, 2-phenylethyl, furan-3-ylmethyl,pyridin-2-ylmethyl, (1R)-1-phenylethyl, benzyl, phenyl, 4-fluorobenzyl,4-methoxybenzyl, 4-methylbenzyl, bicyclo[2.2.1]hept-2-ylmethyl,tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-ylmethyl,(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl,(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl,(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl,(1S,2S,4R)-bicyclo[2.2.1]hept-2-yl,(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl, (2R)-tetrahydrofuran-2-ylmethyl, (2S)-bicyclo[2.2.1]hept-2-yl],[(2S)-tetrahydrofuran-2-ylmethyl, (3R)-tetrahydrofuran-3-yl,(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl, bicyclo[2.2.1]hept-2-yl,cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, cyclohexylmethyl,cyclopentylmethyl, cyclopropylmethyl, adamantan-1-yl, 2-adamantyl,bicyclo[2.2.1]hept-2-yl, or(6,6-dimethyl-bicyclo[3.1.1]hept-2-yl)-methyl.

In some embodiments, where Y is CH and Z is CH or N, R¹ is

or

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N,

is

In some embodiments, where Y is CH and Z is CH or N, R^(a) is H.

In some embodiments, where Y is CH and Z is CH or N, R^(b) is H ormethyl.

In some embodiments, where Y is CH and Z is CH or N, R^(c) is H or

methyl. In some embodiments, where Y is CH and Z is CH or N, R² is —CH₃.

In some embodiments Y and Z are CH.

In some embodiments Y and Z is N.

Some further embodiments are given by compounds of Formula (I) where Yis N, Z is CH, and R¹ is C₁₋₈alkyl (unsubstituted or substituted with—OH or —CF₃), phenyl, pyridyl, benzyl, pyridin-2-ylmethyl, phenylethyl,1-phenyl-ethyl (each independently unsubstituted or substituted withhalo, —CH₃, —OCH₃), cycloalkyl, —(CH₂)-(monocyclic cycloalkyl),—(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH₂)-(bridged polycyclic cycloalkyl), —(CH₂)₀₋₁tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl (each independently unsubstituted orsubstituted with one, two, or three C₁₋₄alkyl substituents). In some ofthese embodiments, R¹ is 2,2-dimethylpropanol, 2,2-dimethylpropan-1-ol,2,2-dimethylpropyl, 2-methyl-1-propan-2-ol, 2-methylpropan-2-ol,3-propanol, (1-methylethyl), 2,2-dimethylpropyl, 2-methoxyethyl,2-methylpropyl, 4,4,4-trifluorobutyl, propyl, butyl, tert-butyl,propan-1-ol, 2-(methylsulfanyl)ethyl, 2-phenylethyl, furan-3-ylmethyl,pyridin-2-ylmethyl, (1 R)-1-phenylethyl, benzyl, phenyl, 4-fluorobenzyl,4-methoxybenzyl, 4-methylbenzyl, bicyclo[2.2.1]hept-2-ylmethyl,tetrahydro-2H-pyran-4-yl, tetrahydrofuran-2-ylmethyl,(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl,(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl,(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl,(1S,2S,4R)-bicyclo[2.2.1]hept-2-yl,(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl,(2R)-tetrahydrofuran-2-ylmethyl, (2S)-bicyclo[2.2.1]hept-2-yl],[(2S)-tetrahydrofuran-2-ylmethyl, (3R)-tetrahydrofuran-3-yl,(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl, bicyclo[2.2.1]hept-2-yl,cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, cyclohexylmethyl,cyclopentylmethyl, cyclopropylmethyl, adamantan-1-yl, 2-adamantyl,bicyclo[2.2.1]hept-2-yl, or(6,6-dimethyl-bicyclo[3.1.1]hept-2-yl)-methyl.

In some embodiments, where Y is N and Z is CH, R¹ is

Or

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH,

is

In some embodiments, where Y is N and Z is CH, and R^(a) is H.

In some embodiments, where Y is N and Z is CH, R^(b) is H or methyl.

In some embodiments, where Y is N and Z is CH, R^(c) is H or methyl.

In some embodiments, where Y is N and Z is CH, R² is —CH₃.

In some embodiments, where Y is N and Z is CH.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove and of the specific compounds exemplified herein, and methodsusing such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn, etal., “Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database”, J. Med. Chem., 2007, 50: 6665-72,S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection,and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, y-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acidor glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

Where the compound of Formula (I) contains a plurality of basicnitrogens, one skilled in the art will recognize that suitable saltsinclude salts formed with one or more equivalents of an inorganic ororganic acid. In preferred embodiments of Formula (I), such saltsinclude bis hydrochloride salts.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C_(i-6)alkyl) amines.Secondary amines include 5- or 6-membered heterocycloalkyl or heteroarylring moieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs.

Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxygroups may also provide prodrugs. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may bean alkyl ester, optionally substituted with one or more ether, amine, orcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, is also useful to yield prodrugs.Prodrugs of this type may be prepared as described in Robinson et al.,J. Med. Chem. 1996, 39, 10-18. Free amines can also be derivatized asamides, sulfonamides or phosphonamides. All of these prodrug moietiesmay incorporate groups including ether, amine, and carboxylic acidfunctionalities.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I), and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997,40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites, whether alone or in combination, (collectively, “activeagents”) of the present invention are useful as histamine H₄ receptormodulators in the methods of the invention. Such methods for modulatinghistamine H₄ receptor activity comprise exposing histamine H₄ receptorto an effective amount of at least one chemical entity selected fromcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I), and pharmaceutically active metabolites of compounds ofFormula (I). Embodiments of this invention inhibit histamine H₄ receptoractivity.

In some embodiments, the histamine H₄ receptor is in a subject diagnosedwith or suffering from a disease, disorder, or medical conditionmediated through histamine H₄ receptor activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “medical conditions, disorders, or diseases.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated through histamine H₄ receptoractivity, such as inflammation. Active agents according to the inventionmay therefore be used as anti-inflammatory agents. Active agentsaccording to the invention may also be used for the treatment of pain.

In some embodiments, an active agent of the present invention isadministered to treat inflammation. Inflammation may be associated withvarious diseases, disorders, or conditions, such as inflammatorydisorders, allergic disorders, dermatological disorders, autoimmunedisease, lymphatic disorders, and immunodeficiency disorders, includingthe more specific conditions and diseases given below. Regarding theonset and evolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Treatment of inflammation according to this invention includes topicaltreatments. For example, topical treatments of conditions such aspruritus, urticaria, and atopic dermatitis.

Illustrative types of inflammation treatable with a histamine H₄receptor-modulating agent according to the invention includeinflammation due to any one of a plurality of conditions such asallergy, asthma, dry eye, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis (see: Ohki, E. et al. Biol. Pharm.Bull. 2007, 30(11), 2217-2220), multiple sclerosis, inflammatory boweldiseases (including colitis, Crohn's disease, and ulcerative colitis),psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria (hives),ocular inflammation (e.g., post-surgical ocular inflammation),conjunctivitis, dry eye, nasal polyps, allergic rhinitis, nasal itch,scleroderma, autoimmune thyroid diseases, post-operative adhesion (See:U.S. Pat. Appl. Publ. 2007/0185163), and immune-mediated (also known astype 1) diabetes mellitus and lupus, which are characterized byexcessive or prolonged inflammation at some stage of the disease.Treatment of metabolic disorders, such as type 2 diabetes, is alsoenvisaged within the scope of this invention. Treatment of othermetabolic disorders envisaged within the scope of this invention includechronic renal failure, hepatic cholestasis, and diabetes mellitus.

Other autoimmune diseases that lead to inflammation include Myastheniagravis, autoimmune neuropathies, such as Guillain-Barré, autoimmuneuveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides, such as Wegener's granulomatosis, Behcet's disease,dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliarycirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland, polymyositis, dermatomyositis,spondyloarthropathies, such as ankylosing spondylitis, and Sjogren'ssyndrome.

Pruritis treatable with a histamine H₄ receptor-modulating agentaccording to the invention includes that which is a symptom of allergiccutaneous diseases (such as atopic dermatitis and hives).

Treatment of mood and anxiety disorders is also envisaged within thescope of this invention. Examples of such mood disorders include majordepression disorder, bipolar disorder, treatment-resistant majordepression disorder, and treatment-resistant bipolar disorder. Examplesof such anxiety disorders include generalized anxiety disorder, socialphobia, and post traumatic stress disorder.

In other embodiments, an active agent of the present invention isadministered to treat allergy, rheumatoid arthritis, asthma, autoimmunediseases, or pruritis.

Thus, the active agents may be used to treat subjects diagnosed with orsuffering from a disease, disorder, or condition mediated throughhistamine H₄ receptor activity. The term “treat” or “treating” as usedherein is intended to refer to administration of an active agent orcomposition of the invention to a subject for the purpose of effecting atherapeutic or prophylactic benefit through modulation of histamine H₄receptor activity. Treating includes reversing, ameliorating,alleviating, inhibiting the progress of, lessening the severity of, orpreventing a disease, disorder, or condition, or one or more symptoms ofsuch disease, disorder or condition mediated through modulation ofhistamine H₄ receptor activity. The term “subject” refers to a mammalianpatient in need of such treatment, such as a human. Some embodiments ofthis invention are envisaged for veterinary use. “Modulators” includeboth inhibitors and activators, where “inhibitors” refer to compoundsthat decrease, prevent, inactivate, desensitize or down-regulatehistamine H₄ receptor expression or activity, and “activators” arecompounds that increase, activate, facilitate, sensitize, or up-regulatehistamine H₄ receptor expression or activity.

In treatment methods according to the invention, an effective amount ofat least one active agent according to the invention is administered toa subject suffering from or diagnosed as having such a disease,disorder, or condition. An “effective amount” means an amount or dosesufficient to generally bring about the desired therapeutic orprophylactic benefit in patients in need of such treatment for thedesignated disease, disorder, or condition. Effective amounts or dosesof the active agents of the present invention may be ascertained byroutine methods such as modeling, dose escalation studies or clinicaltrials, and by taking into consideration routine factors, e.g., the modeor route of administration or drug delivery, the pharmacokinetics of theagent, the severity and course of the disease, disorder, or condition,the subject's previous or ongoing therapy, the subject's health statusand response to drugs, and the judgment of the treating physician. Anexemplary dose is in the range of from about 0.001 to about 200 mg ofactive agent per kg of subject's body weight per day, preferably about0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 1 to 200 mg/day, or about 5 to 50 mg/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of Formula (I) orincluded with such an agent in a pharmaceutical composition according tothe invention. In an exemplary embodiment, additional active ingredientsare those that are known or discovered to be effective in the treatmentof conditions, disorders, or diseases mediated by histamine H₄ receptoractivity, such as another histamine H₄ receptor modulator or a compoundactive against another target associated with the particular condition,disorder, or disease. The combination may serve to increase efficacy(e.g., by including in the combination a compound potentiating thepotency or effectiveness of an agent according to the invention),decrease one or more side effects, or decrease the required dose of theactive agent according to the invention.

When referring to modulating the target receptor, an “effective amount”means an amount sufficient to affect the activity of such receptor.Measuring the activity of the target receptor may be performed byroutine analytical methods. Target receptor modulation is useful in avariety of settings, including assays.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention; and optionally(b) a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., from about 0.05 to about 50mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Each of the reactions depicted in Scheme A ispreferably run at a temperature from about room temperature to thereflux temperature of the organic solvent used. Unless otherwisespecified, the variables are as defined above in reference to Formula(I).

As shown in Scheme A, compounds of Formula (I) are prepared bysequential reaction of compounds (X) with amines (XI) and amines (XIII).Where Y and Z are CH, Hal¹ is chloro, and Hal² is chloro, bromo, oriodo, addition of amines (XI) by palladium-catalyzed amination givescompounds (XII). Amination reactions are performed in the presence of apalladium(0) catalyst such as tris(dibenzylidene-acetone)dipalladium(0)(Pd₂(dba)₃), or tetrakis(triphenylphosphine)palladium, a ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos),1,1′-bis(diphenylphosphino)ferrocene (dppf),2,2′-bis(diphenylphosphino)-1,1′-bihaphthyl (BINAP), Cy-MAP[(2′-dicyclohexylphosphanylbiphen-2-yl)dimethylamine], Cy₂P(Ph-Ph)(dicyclohexyl-2-biphenylphosphane), tBu₂P(Ph-Ph)(di-tert-butyl-2-biphenylphosphane), tBu₃P, or IPrHCl(IPr=1,4-bis(2,6-diisopropyl)imidazol-2-ylidene), and a base such assodium tert-butoxide, potassium tert-butoxide, lithium or sodiumbis(trimethylsilyl)amide, or Cs₂CO₃, in a solvent such as toluene,tetrahydrofuran (THF), dimethylacetamide (DMA), dimethoxyethane (DME),or tert-butanol, or a mixture thereof, at a temperature from about 50°C. to about 140° C. (Ji et al. J. Org. Chem. 2003, 24, 4611-4614).Preferably, reactions are performed using Pd₂(dba)₃, Xantphos, andsodium tert-butoxide, in toluene, at a temperature of about 70° C. toabout 110° C.

Compounds (XII) where Y and Z are CH and Hal¹ is chloro are subsequentlyconverted to pyridines of Formula (I) by palladium-catalyzed aminationwith amines (XIII), as described above. Preferably, reactions areperformed using palladium(II) acetate (Pd(OAc)₂), BINAP, and sodiumtert-butoxide, in toluene, DMA, or tert-butanol (or a mixture thereof),at a temperature of about 50° C. to about 110° C.

Where Y is CH and Z is N, Hal¹ is chloro, and Hal² is chloro, bromo, oriodo, compounds (X) are reacted by displacement with amines (XI), withor without the presence of a tertiary amine base (such asdiisopropylethylamine or triethylamine), in an organic solvent such asmethanol, ethanol, isopropanol, tert-amyl alcohol, pentan-1-ol, THF, oracetonitrile, or a mixture thereof, at a temperature of about 0° C. toabout 180° C., either by traditional heating or under microwaveconditions to provide compounds of formula (XII). Compounds (XII) whereY is CH and Z is N and Hal¹ is chloro are subsequently reacted withamines (XIII) using displacement conditions as described to providepyrimidines of Formula (I).

Additionally, compounds of Formula (I) are prepared by sequentialreaction of compounds (X) with amines (XI) and amines (XIII). Compounds(X) where Y is N and Z is CH, Hal¹ and Hal² are chloro, are reacted withamines), with or without the presence of a tertiary amine base (such asdiisopropylethylamine or triethylamine), in a solvent such as THF or DMFand the like, at a temperature of about 23° C. to about 110° C., toprovide compounds (XII). Addition of amines (XIII) either bypalladium-catalyzed amination, as described, or by displacement of thechlorine with the amine (XIII) neat or in a polar solvent such as DME,with or without the presence of a tertiary amine base (such asdiisopropylethylamine or triethylamine) at temperatures ranging from100° C. to 250° C. under conventional heating or microwave conditions,provides pyridazines of Formula (I).

As shown in Scheme B, compounds of Formula (I) are prepared bysequential reaction of compounds (XIV) with amines (XIII) and amines(XI). Compounds (XIV) where Y and Z are CH, Hal³ is fluoro and Hal⁴ isiodo or bromo, are reacted with amines (XIII) in a polar solvent such asN-methylpyrrolidinone (NMP), N,N-dimethylformamide, DMA,dimethylsulfoxide, or a mixture thereof, at a temperature of about 50°C. to about 110° C., either by traditional heating or under microwaveconditions to provide compounds (XV). Addition of amines (XI) either bypalladium-catalyzed amination (as described for Scheme A) or bynucleophilic aromatic substitution in the presence of a Lewis acid suchas ytterbium trifluormethanesulfonate (Yb(OTf)₃), in a polar solventsuch as DMA or NMP, at a temperature of about 150° C. to about 250° C.under conventional heating or microwave conditions, provides pyridinesof Formula (I).

Compounds (XIV) where Y is CH and Z is N, Hal³ is chloro, and Hal⁴ ischloro, are reacted by displacement with amines (XIII) to give compounds(XV) and then with amines (XI) to give pyrimidines of Formula (I).Displacement reactions are performed as described for Scheme A.

As shown in Scheme C, compounds (XVII), where Y is N, Z is C, and Hal¹is chloro, are prepared by chlorination of compounds (XVI) usingconditions know to one skilled in the art, for example, by reaction withphosphoryl chloride, at temperatures ranging from 65° C. to about 120°C. afford compounds (XVII). Compounds (XVII) are reacted by displacementwith amines (XI), with a tertiary amine base (such asdiisopropylethylamine or triethylamine), in an organic solvent such asmethanol, ethanol, isopropanol, tert-amyl alcohol, pentan-1-ol, THF, oracetonitrile, or a mixture thereof, at a temperature of about 23° C. to180° C., either by traditional heating or under microwave conditions.Compounds (XVIII) are subsequently reacted with amines (XIII) usingdisplacement conditions as described to provide pyridazines (XIX).Reaction of halo-pyridazines (XIX) with a reducing agent such as 10%palladium on carbon, in the presence of ammonium formate, in a polarsolvent such as methanol, at temperatures ranging from 65° C. to 85° C.provides compounds of Formula (I).

As shown in Scheme D, compounds (XVI), where Y is N, Z is C, and Hal¹ ischloro, are reacted with hydrogen iodide acid (57%), at temperaturesranging from 100° C. to 150° C. to provide 5-iodo-4H-pyridazin-3-oneintermediate (XXI). Subsequent reaction of intermediate (XXI) withamines (XI) in a displacement fashion, in an organic solvent such asmethanol, ethanol, isopropanol, tert-amyl alcohol, pentan-1-ol, THF, oracetonitrile, or a mixture thereof, at a temperatures ranging from 23°C. to 180° C., either by traditional heating or under microwave heatingprovide compounds of formula (XXII). Chlorination of compounds (XXII)using conditions known to one skilled in the art, for example, byreaction with phosphoryl chloride, at temperatures ranging from 65° C.to about 120° C. afford compounds (XXIII). Compounds (XXIII) are reactedwith amines (XIII) in a displacement reaction, in an organic solventsuch as methanol, ethanol, isopropanol, tert-amyl alcohol, pentan-1-ol,THF, or acetonitrile, or a mixture thereof, at a temperature of about23° C. to 200° C., either by traditional heating or under microwaveheating provide compounds of Formula (I).

In the above Schemes, where the diamine HNR³R⁴ (XIII) contains anitrogen protecting group (PG), such as a tert-butoxycarbonyl (Boc)group or benzyl group, in place of the R^(a) or R^(c) substituent, theprotecting group is removed by deprotection conditions known to oneskilled in the art, to provide compounds where R^(a) or R^(c) is H. Forexample, a tert-butoxycarbonyl group is removed using an organic acidsuch as TFA (neat or in a solvent such as CH₂Cl₂) or an inorganic acidsuch as HCl (in a solvent such as 1,4-dioxane, ether, methanol,isopropanol, or formic acid, or a mixture thereof). Reductive aminationor alkylation procedures may be used to convert compounds where R^(c) isH to compounds where R^(c) is C₁₋₃alkyl.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods described in the art. For example, an amine of Formula

(I) is treated with trifluoroacetic acid, HCl, or citric acid in asolvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, or isopropanol toprovide the corresponding salt form. Alternately, trifluoroacetic acidor formic acid salts are obtained as a result of reverse phase HPLCpurification conditions. Cyrstalline forms of pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained incrystalline form by recrystallization from polar solvents (includingmixtures of polar solvents and aqueous mixtures of polar solvents) orfrom non-polar solvents (including mixtures of non-polar solvents).

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions are“dried,” they are generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Silica gel (SiO₂) was used for flash chromatographicpurification (FCC) and the eluent used is listed in parentheses.

Microwave heating was performed on a Personal Chemistry Emrys™ Optim/zerusing Biotage microwave vials.

Analytical reversed-phase high-performance liquid chromatography (HPLC)was performed on a Hewlett Packard HPLC Series 1100, with a PhenomenexONYX® monolithic C18 (5 μm, 4.6×100 mm) column. Detection was done atλ=230, 254 and 280 nm. The flow rate was 1 mL/min. The gradient was 10to 90% acetonitrile/water (20 mM NH₄OH) over 5.0 min. Preparativereversed-phase HPLC was performed on a Dionex instrument equipped with aYMC Pack ODS 250×30 mm column with a gradient of 10 to 50% NH₄OH inacetonitrile (0.05% water) over 15 min at a flow rate of 70 mL/min.Alternatively, compounds were purified on a Waters LC/MS equipped with aWaters XBridge C18 column (100×30 mm) with a gradient of 1 to 25%acetonitrile/water (0.05% trifluoroacetic acid (TFA)) over 15 min at aflow rate of 44 mL/min. Analytical reversed-phase HPLC was performed onAgilent HPLC with C18 (5 μm, 4.6×150 mm) column. Detection was done atλ=214 and 254 nm. The flow rate was 1 mL/min. The gradient was 10 to 90%acetonitrile/water (0.1% formic Acid) over 10 min.

Preparative thin-layer chromatography (TLC) was performed using 20×20 cmsilica gel 60 F₂₅₄ plates, with a 0.5 mm thickness.

Preparative reversed-phase HPLC was performed on Gemini column C18(150×21.2 mm) with a gradient of 5 to 60% acetonitrile and water (0.1%trifluoroacetic acid or 0.1% formic acid) over 14 min at a flow rate 20mL/min monitored at 214 nm.

Compounds were analyzed in a free-base, hydrochloride ortrifluoroacetate salt form. Hydrochloride salts were obtained either: 1)during the removal of the tert-butylcarbamoyl (Boc) group; or 2) bytreatment of a solution of the purified free base in THF, CHCl₃ orCH₂Cl₂ (DCM) with at least two equivalents of a solution of HCl in1,4-dioxane or ether followed by concentration. TFA salts were obtaineddirectly from HPLC purification.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers (400 MHz or 500 MHz) or Varian (300 MHz) spectrometer.The format of the ¹H NMR data below is: chemical shift in ppm downfieldof the tetramethylsilane reference (multiplicity, coupling constant J inHz, integration).

Mass spectra were obtained on an Agilent series 1100 MSD or 1200 MSDusing electrospray ionization (ESI) in either positive or negative modesas indicated. The MS data presented is the m/z found (typically [M+H]⁺)for the molecular ion.

Chemical names were generated using ACD/Name Version 10 (AdvancedChemistry Development, Toronto, Ontario, Canada) or ChemDraw Version6.0.2 (CambridgeSoft, Cambridge, Mass.).

Example 1Bicyclo[2.2.1]hept-2-yl44-((3R)-3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-aminedihydrochloride

(3R)-[1-(2-Chloro-pyridin-4-yl)-pyrrolidin-3-yl]methyl-amine. To astirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.1 mmol) intoluene (100 mL) was added (R)-methyl-pyrrolidin-3-yl-amine (1.7 g, 17.0mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask wasevacuated and flushed with N_(2(g)) twice. A mixture of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 590 mg, 1.0mmol) and tris(dibenzylideneacetone)-dipalladium(0) (Pd₂(dba)₃; 310 mg,0.34 mmol) was added in one portion and the mixture was heated at 85° C.for 20 h. The mixture was cooled to room temperature (rt), diluted withH₂O (75 mL), and extracted with ethyl acetate (EtOAc; 3×). The combinedorganic layers were dried and concentrated to give a clear brown oil.The oil was purified by FCC (0 to 5% 2 M NH₃ in MeOH/CH₂Cl₂) to give thetitle compound as a brown solid (1.1 g, 30%). MS (ESI): mass calcd. forC₁₀H₁₄CIN₃, 211.09 m/z found, 212.1 [M+H]. ¹H NMR (DMSO-d₆): 7.86 (d,J=5.9, 1H), 6.47-6.38 (m, 2H), 3.45-3.17 (m, 4H), 3.11-3.01 (m, 1H),2.29 (s, 3H), 2.15-2.00 (m, 1H), 1.82 (br s, 1H), 1.79-1.65 (m, 1H).Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine.To a stirring mixture of[(3R)-1-(2-chloro-pyridin-4-yl)-pyrrolidin-3-yl]-methyl-amine (97 mg,0.46 mmol), exo-2-aminonorbornane (164 pL, 1.4 mmol) in ethylene glycoldimethyl ether (DME; 4 mL) in a scintillation vial was added sodiumtert-butoxide (245 mg, 2.6 mmol). To the stirring mixture was added inone portion Pd(OAc)₂ (16 mg, 0.024 mmol) and racemic2,2′-bis(diphenylphosphino)-1,1′-bihaphthyl (BINAP; 19 mg, 0.031 mmol).The mixture was heated at 65° C. for 20 h, then was cooled to rt andfiltered through a plug of diatomaceous earth. The plug was washed withMeOH (2 mL) and the filtrate was purified directly by FCC (5% 2 M NH₃ inMeOH/CH₂Cl₂) to give a clear light golden oil (70 mg, 54%).Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine.To a stirring solution ofbicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]aminein 1:1 Et₂O/CH₂Cl₂ (8 mL) was added 1 N HCl in Et₂O (1 mL). The organiclayers was separated and concentrated to give the desired product (89mg, 100%) as a beige solid. MS (ESI): mass calcd. for C₁₇H₂₆N₄, 286.2;m/z found, 287.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 12.07 (s, 1H), 9.57 (br s,1H), 9.46 (br s, 1H), 7.81 (d, J=5.1, 1H), 7.66 (d, J=4.6, 1H), 6.28 (d,J=7.4, 1H), 5.64 (s, 1H), 3.89 (br s, 1H), 3.85-3.61 (m, 3H), 3.49 (brs, 2H), 2.60 (s, 3H), 2.35-2.20 (m, 3H), 2.18 (s, 1H), 1.95-1.85 (m,1H), 1.55-1.46 (m, 3H), 1.37-1.25 (m, 2H), 1.21-1.09 (m, 2H).

The compounds in Example 2 through Example 15 were prepared usingmethods analogous to those described for Example 1.

Example 2N-Cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.2; m/z found, 261.3 [M+H]⁺. ¹HNMR (DMSO-d₆): 7.57 (d, J=5.9, 1H), 5.77 (dd, J=5.9, 2.1, 1H), 5.72 (d,J=7.1, 1H), 5.42 (s, 1H), 4.05-3.96 (m, 1H), 3.36-3.29 (m, 2H),3.28-3.15 (m, 2H), 2.99-2.91 (m, 1H), 2.29 (s, 3H), 2.06-1.98 (m, 1H),1.90-1.81 (m, 2H), 1.81-1.72 (m, 2H), 1.71-1.62 (m, 2H), 1.55-1.46 (m,2H), 1.45-1.35 (m, 2H).

Example 34-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-propylpyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 260.2; m/z found, 235.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.12 (s, 1H), 9.46-9.26 (m, 2H), 7.71 (d, J=5.2, 1H),7.65 (d, J=6.9, 1H), 6.29 (d, J=7.4, 1H), 5.68 (s, 1 H), 3.90 (br s,1H), 3.78-3.61 (m, 3H), 3.37 (br s, 1H), 3.28-3.16 (m, 2H), 2.61 (s,3H), 2.46-2.21 (m, 2H), 1.58 (q, J=7.3, 2H), 0.95 (t, J=7.4, 3H).

Example 4N-(Cyclopropylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amineditrifluoroacetate

MS (ESI): mass calcd. for C₁₄H₂₂N₄, 246.2; m/z found, 247.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.00 (s, 1H), 8.96 (s, 2H), 7.74 (d, J=5.1, 1H), 7.66(d, J=4.3, 1H), 6.30 (d, J=7.4, 1H), 5.71 (s, 1H), 3.94 (br s, 2H), 3.60(br s, 2H), 3.12 (d, J=6.8, 2H), 2.67 (s, 3H), 2.51-2.42 (m, 2H),2.42-2.36 (m, 1H), 1.58-1.46 (m, 1H), 0.53 (d, J=8.0, 2H), 0.27 (d,J=6.1, 2H).

Example 54-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₄H₂₂N₄O, 262.2; m/z found, 263.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.14 (s, 1H), 9.55 (br s, 1H), 9.48 (s, 1H), 7.99 (d,J=7.1, 1H), 7.68 (d, J=7.1, 1H), 7.48 (s, J=8.0, 0.5H), 7.12 (d, J=8.4,0.5H), 6.32 (d, J=7.4, 1H), 5.73 (s, 1H), 4.35-4.21 (m, 1H), 3.95-3.79(m, 3H), 3.82-3.70 (m, 2H), 3.66-3.50 (m, 2H), 2.61 (t, J=5.1, 3H),2.45-2.21 (m, 4H), 1.88-1.74 (m, 1H).

Example 64-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[tetrahydrofuran-2-ylmethyl]pyridin-2-aminedihydrochloride

The title compound was prepared as a mixture of diastereomers. MS (ESI):mass calcd. for C₁₅H₂₄N₄O, 276.2; m/z found, 277.2 [M+H]⁺. ¹H NMR(DMSO-d₆): 12.34 (s, 1H), 9.63 (br s, 1H), 9.60 (s, 1H), 7.75-7.61 (m,2H), 6.27 (d, J=7.4, 1 H), 5.77 (s, 1H), 4.05-3.96 (m, 1 H), 3.96-3.83(m, 1H), 3.82-3.61 (m, 6H), 3.38-3.30 (m, 2H), 2.58 (s, 3H), 2.48-2.38(m, 2H), 2.04-1.85 (m, 3H), 1.78-1.72 (m, 1H).

Example 7N-(4-Fluorobenzyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₇H₂₁FN₄, 300.2; m/z found, 301.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.39 (s, 1H), 9.38 (br s, 2H), 8.15 (t, J=6.0, 1H), 7.68(d, J=7.1, 1H), 7.48-7.38 (m, 2H), 7.25-7.13 (m, 2H), 6.29 (d, J=7.4,1H), 5.73 (s, 1H), 4.52 (d, J=6.0, 2H), 3.96 (br s, 1H), 3.92-3.38 (m,4H), 2.59 (s, 3H), 2.42-2.21 (m, 2H).

Example 8N-Cyclopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₃H₂₀N₄, 232.2; m/z found, 233.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.21 (s, 1H), 9.58 (br s, 2H), 8.28 (d, J=5.4, 0.35H),8.19 (s, 1H), 7.70 (s, 0.65H), 6.90 (d, J=7.4, 0.65H), 6.35 (d, J=7.4,0.65H), 5.78 (s, 1H), 4.02-3.33 (m, 6H), 2.60 (s, 3H), 2.43-2.25 (m,2H), 0.88-0.86 (m, 2H), 0.56-0.50 (m, 2H).

Example 9 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-R1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5; m/z found, 329.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.56 (d, J=6.2, 1H), 5.93 (dd, J=6.2, 2.2, 1H), 5.56 (d, J=2.1, 1H), 4.80 (s, 4H), 3.99 (dt, J=9.4, 6.3, 1H), 3.52 (dd, J=10.0,6.4, 1H), 3.49-3.40 (m, 1H), 3.38-3.27 (m, 4H), 3.11 (dd, J=10.0, 5.2,1H), 2.71-2.61 (m, 1H), 2.46-2.37 (m, 1H), 2.23 (td, J=13.6, 5.9, 1H),2.01-1.77 (m, 4H), 1.58 (ddd, J=13.8, 5.6, 2.4, 1 H), 1.24 (d, J=8.9,3H), 1.13 (t, J=7.4, 3H), 1.10 (s, 3H), 1.03 (d, J=9.7, 1H).

Example 104-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-R1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5; m/z found, 329.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.56 (d, J=6.2, 1H), 5.95 (dd, J=6.3, 2.2, 1H), 5.57 (d, J=2.1, 1H), 3.99 (dt, J=9.4, 6.3, 1 H), 3.52 (dd, J=10.0, 6.3, 1H), 3.46(dd, J =14.7, 8.9, 1H), 3.39-3.28 (m, 6H), 3.13 (dd, J=10.0, 5.1, 1H),2.67 (t, J =11.6, 1 H), 2.47-2.37 (m, 1H), 2.23 (td, J=13.7, 5.9, 1H),2.02-1.78 (m, 4H), 1.58 (ddd, J=13.8, 5.6, 2.4, 1H), 1.26 (s, 3H), 1.14(d, J=7.2, 3H), 1.10 (s, 3H), 1.03 (d, J=9.7, 1H).

Example 11N-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₂N₄, 282.4; m/z found, 283.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.57 (d, J=6.1, 1H), 7.36-7.32 (m, 2H), 7.31-7.26 (m, 2H),7.20 (t, J=7.2, 1H), 5.93 (dd, J=6.2, 2.2, 1H), 5.51 (d, J=2.1, 1H),4.41 (s, 2H), 3.44 (dd, J=10.0, 6.4, 1H), 3.41-3.32 (m, 1H), 3.28-3.19(m, 1H), 3.04 (dd, J=10.0, 5.1, 1H), 2.27-2.10 (m, 1H), 1.93-1.76 (m,1H).

Example 124-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(1-methylethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.4; m/z found, 235.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.56 (d, J=6.2, 1H), 5.92 (dd, J=6.2, 2.2, 1H), 5.53 (d, J=2.1, 1H), 3.82 (hept, J=6.4, 1H), 3.51 (dd, J=10.0, 6.4, 1H), 3.48-3.40(m, 1H), 3.38-3.26 (m, 2H), 3.10 (dd, J=10.0, 5.2, 1H), 2.27-2.17 (m,1H), 1.96-1.79 (m, 1H), 1.18 (d, J=6.4, 6H).

Example 134-[(3R)-3-Aminopyrrolidin-1-yl]-N-(1-methylethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₀N₄, 220.3; m/z found, 221.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.55 (d, J=7.4, 1H), 6.35 (dd, J=7.4, 2.4, 1H), 5.74 (d, J=2.3, 1H), 4.12 (s, 1H), 3.83 (dt, J=12.7, 6.4, 2H), 3.78-3.66 (m, 1H),3.66-3.54 (m, 2H), 3.40-3.24 (m, 4H), 2.53 (dd, J=14.9, 6.5, 1H), 2.26(d, J=5.3, 1H), 1.28 (d, J=6.4, 6H).

Example 144-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.4; m/z found, 235.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.49 (d, J=7.3, 1H), 6.23 (dd, J=7.3, 2.4, 1H), 5.64 (d, J=2.3, 1H), 3.78-3.69 (m, 1H), 3.66-3.56 (m, 2H), 3.51-3.41 (m, 1H),3.33-3.27 (m, 1H), 3.20 (dd, J=10.8, 4.5, 1H), 3.06 (d, J=6.9, 2H),2.32-2.20 (m, 1H), 1.97-1.85 (m, 2H), 1.01 (d, J=6.7, 6H).

Example 154-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₄N₄, 248.4; m/z found, 249.2 [M+H]⁺. ¹HNMR CD₃OD): 7.55 (d, J=6.4, 1H), 6.02 (dd, J=6.5, 2.2, 1H), 5.57 (d, J=2.1, 1H), 3.56 (dd, J=10.2, 6.3, 1H), 3.53-3.46 (m, 1H), 3.42-3.34 (m,2H), 3.16 (dd, J=10.2, 5.1, 1H), 3.03 (d, J=6.9, 2H), 2.34-2.18 (m, 1H),1.91 (m, 2H), 0.99 (d, J=6.7, 6H).

Example 16 N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine

4-(2-Chloro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester.To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.5 mmol) intoluene (100 mL) was added piperazine-1-carboxylic acid tert-butyl ester(3.2 g, 17.2 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). Theflask was evacuated and flushed with N₂(g) twice. A mixture of Xantphos(600 mg, 1.0 mmol) and Pd₂(dba)₃ (318 mg, 0.35 mmol) was added in oneportion and the mixture was heated at 85° C. for 20 h. The mixture wascooled to rt, diluted with H₂O (75 mL), and extracted with EtOAc (3×).The combined organic layers were dried and concentrated to give a cleargolden oil. The oil was purified on FCC (0 to 5% 2 M NH₃ in MeOH/CH₂Cl₂)to give the title product as a beige solid (5.1 g, 100%). MS (ESI): masscalcd. for C₁₄H₂₀CIN₃O₂, 297.1; m/z found, 298.2 [M+H]⁺. ¹H NMR(DMSO-d₆): 7.95 (d, J=5.9, 1H), 6.88-6.78 (m, 2H), 3.46-3.32 (m, 8H),1.42 (s, 9H).

tert-Butyl 4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate.To a stirring solution of4-(2-chloro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester(163 mg, 0.55 mmol) in toluene (2 mL) in a vial was addedcyclopentylamine (136 μL, 1.38 mmol) and sodium tert-butoxide (161 mg,1.68 mmol). A mixture of racemic BINAP (20 mg, 0.032 mmol) and Pd(OAc)₂(18 mg, 0.027 mmol) was added in one portion and the mixture was heatedat 85° C. for 20 h. The mixture was cooled to rt and purified directlyby FCC (0 to 5% 2 M NH₃ in MeOH/CH₂Cl₂) to provide the title compound asa white solid (34 mg, 17%). MS (ESI): mass calcd. for C₁₉H₃₀N₄O₂, 346.2;m/z found, 347.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 7.65 (d, J=6.0, 1 H), 6.10(d, J=6.0, 1H), 5.92 (d, J=7.1, 1H), 5.78 (s, 1H) 4.08-4.02 (m, 1 H),3.41 (t, J=5.4, 4H), 3.16 (t, J=5.4, 4H), 1.89-1.82 (m, 2H), 1.67-1.61(m, 2H), 1.59-1.48 (m, 2H), 1.42 (s, 9H), 1.43-1.35 (m, 2H).

N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine dihydrochloride. To astirring solution of tert-butyl4-[2-(cyclopentylamino)pyridin-4-yl]piperazine-1-carboxylate (34 mg, 0.1mmol) in 96% formic acid (4 mL) was added 6 N aq HCl (2 drops). Themixture was stirred for 2 h and concentrated to give the desired productas a white solid (26 mg, 93%). MS (ESI): mass calcd. for C₁₄H₂₂N₄,246.2; m/z found, 247.2 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.32 (s, 2H), 7.89 (d,J=7.1, 1 H), 7.69 (d, J=7.5, 1H), 6.58 (d, J=7.6, 1H), 6.04 (s, 1H),4.03-3.96 (m, 1H), 3.73 (t, J=4.9, 4H), 3.20 (t, J=5.0, 4H), 2.03-1.95(m, 2H), 1.73-1.68 (m, 2H), 1.64-1.52 (m, 2H), 1.50-1.42 (M, 2H).

The compounds in Example 17 through Example 20 were prepared usingmethods analogous to those described for Example 16.

Example 17 4-Piperazin-1-yl-N-propylpyridin-2-amine dihydrochloride

MS (ESI): mass calcd. for C₁₂H₂₀N₄, 220.2; m/z found, 221.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 9.35 (br s, 2H), 7.87-7.82 (m, 1H), 7.69 (d, J=7.5, 1H),6.57 (dd, J=7.5, 2.4, 1H), 6.05 (s, 1H), 3.79-3.69 (m, 4H), 3.32-3.13(m, 6H), 1.63-1.51 (m, 2H), 0.94 (t, J=7.3, 3H).

Example 18 N-Benzyl-4-piperazin-1-ylpyridin-2-amine dihydrochloride?

MS (ESI): mass calcd. for C₁₆H₂₀N₄, 268.4; m/z found, 269.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.62 (d, J=7.5, 1H), 7.46-7.24 (m, 5H), 6.65 (dd, J=7.5,2.1, 1H), 6.13 (d, J=2.0, 1H), 4.55 (s, 2H), 3.90-3.74 (m, 4H),3.41-3.33 (m, 4H).

Example 19 N-(2-Methylpropyl)-4-piperazin-1-ylpyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.4; m/z found, 235.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.81 (d, J=6.1, 1H), 6.11 (dd, J=6.1, 2.3, 1H), 5.69 (d, J=2.0, 1H), 4.47 (s, 1H), 3.43-3.18 (m, 4H), 3.03 (t, J=6.2, 2H),3.02-2.84 (m, 4H), 1.88 (pent, J=6.7, 1H), 0.99 (d, J=6.7, 6H).

Example 204-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-aminedihydrochloride

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.4; m/z found, 235.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.54 (d, J=6.3, 1H), 5.97 (dd, J=6.4, 2.2, 1H), 5.53 (d, J=2.1, 1 H), 3.67-3.60 (pent, J=5.5, 1H), 3.56-3.45 (m, 2H), 3.39-3.32(m, 1H), 3.06 (dd, J=10.0, 4.9, 1H), 3.01 (d, J=6.9, 2H), 2.28-2.14 (m,1H), 1.94-1.78 (m, 2H), 0.98 (d, J=6.7 Hz, 6H).

Example 21 4-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridin-2-amine

Method A

(4-lodo-pyridin-2-yl)-isobutyl-amine. A solution of2-fluoro-4-iodopyridine (2.2 g, 1.0 mmol) in N-methylpyrrolidinone (10mL) at rt was treated with isobutylamine (2.5 mL, 2.5 mmol) and themixture was heated at 100° C. for 6 h. The mixture was cooled to rt,diluted with EtOAc (50 mL), and washed with water (2×10 mL). Thecombined aqueous extracts were back-extracted with EtOAc and thecombined organic layers were dried and concentrated to yield a thick oilwhich solidified on standing (2.6 g, 95%). The solid was used withoutfurther purification. ¹H NMR (CDCl₃): 7.72 (d, J=5.3, 1H), 6.89 (dd,J=5.3, 1.4, 1H), 6.77 (d, J=1.1, 1H), 4.58 (s, 1H), 3.04 (dd, J=6.8,5.9, 2H), 1.87 (dp, J=13.4, 6.7, 1H), 0.98 (d, J=6.7, 6H).

4-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridin-2-amine. Asuspension of (4-iodo-pyridin-2-yl)-isobutyl-amine (78 mg, 0.3 mmol),N-methyl piperazine (0.04 mL, 0.4 mmol)2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) (5.4 mg,4 mol %), Pd₂dba₃ (3.2 mg, 2 mol %) in THF (1 mL) was treated withlithium bis(trimethylsilyl)amide (1.0 M in THF; 0.8 mL, 0.8 mmol) andheated at 65° C. for 16 h. The resulting solution was cooled to rt andconcentrated to minimum volume, then purified directly by FCC (0 to 10%2 M NH₃ in MeOH/CH₂Cl₂) to yield the desired product (29 mg, 41%). MS(ESI): mass calcd. for C₁₄H₂₄N₄, 248.4; m/z found, 249.3 [M+H]⁺. ¹H NMR(CDCl₃): 7.79 (d, J=6.1, 1 H), 6.12 (dd, J=6.2, 2.3, 1H), 5.69 (d,J=2.2, 1H), 4.62 (s, 1H), 3.54-3.23 (m, 4H), 3.03 (dd, J=6.7, 5.8, 2H),2.59-2.22 (m, 7H), 1.89 (dp, J=13.4, 6.7, 1H), 1.19-0.78 (m, 6H).

Method B

4-bromo-N-isobutylpyridin-2-amine. A solution of4-bromo-2-fluoropyridine (352 mg, 2 mmol) and 2-methylpropan-1-amine(584 mg, 8 mmol) in N-methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at100° C. for 1 hr. The reaction was allowed to cool to room temperatureand diluted with DCM (50 mL), washed with water (10 mL * 2). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography (0-20% EtOAc-petrolumn ether gradientelution) to afford the desired product as oil (382mg, 83%). ¹H NMR (300MHz, CDCl₃): 7.86 (d, J=5.1 Hz, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.53 (s,1H), 4.75 (s, 1H), 3.03 (dd, J=6.6 Hz, 6.0 Hz, 2H), 1.88-1.86 (m, 1H),0.98 (s, 3H), 0.96 (s, 3H); LC-MS: m/z=229.2, 231.2 [M+H]⁺.

N-isobutyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine. A mixture of4-bromo-N-isobutylpyridin-2-amine (153 mg, 0.7 mmol), 1-methylpiperazine(80 mg, 0.8 mmol), Pd₂(dba)₃ (6.1 mg, 0.007 mmol) and X-phos (12.7 mg,0.028 mmol) in anhydrous THF (4 mL) was treated with LiHMDS (1.0M, 2.0mL, 2 mmol) under atmosphere of nitrogen. The resulting reaction wasstirred at 65° C. for 3 hrs and diluted with DCM (20 mL), washed withwater (4 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (0-10%MeOH-DCM gradient elution) to afford the desired product (60 mg, 34%).¹H NMR (300 MHz, CDCl₃): 7.74 (d, J=6.6 Hz, 1H), 6.12 (d, J=6.3 Hz, 1H),5.66 (s, 1H), 3.31 (t, J=5.4 Hz, 4H), 3.01 (d, J=6.0 Hz, 2H), 2.51 (t,J=5.4 Hz, 4H), 2.34 (s, 3H), 1.90-1.88 (m, 1H), 1.00 (s, 3H), 0.98 (s,3H); LC-MS: m/z=249.1 [M+H]⁺.

N-isobutyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine dihydrochloride.N-isobutyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine (60mg, 0.24mmol)was dissolved in MeOH (1 mL) and aqueous HCl solution (6N, 0.5 mL) wasadded. The resulting reaction was stirred at 30° C. for 2 hrs. Thereation was concentrated under reduced pressure to afford the desiredproduct (80 mg, 93%). ¹H NMR (300 MHz, DMSO-d₆): 12.59 (s, 1H), 11.49(br s, 1H), 7.97 (s, 1H), 7.72 (m, 1H), 6.60 (d, J=6.9 Hz, 1 H), 6.12(s, 1H), 4.20 (d, J=14 Hz, 2H), 4.00 (br s, 2H), 3.50-3.42 (m, 2H), 3.10(m, 4H), 2.77 (s, 3H), 1.88-1.79 (m, 1H), 0.94 (d, J=6.6 Hz, 6H); LC-MS,m/z=249.2 [M+H]⁺, t_(R)=0.1 min; HPLC: 96% (214 nm), 96% (254 nm),t_(R)=4.5 min.

Example 2244(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine

A solution of (4-iodo-pyridin-2-yl)-isobutyl-amine (96 mg, 0.4 mmol),(3R)-(methylamino)pyrrolidine (0.08 mL, 0.8 mmol), and Yb(OTf)₃ (215 mg,0.4 mmol) in DMA (2 mL) was heated at 200° C. for 2 h in a microwave.The resulting solution was cooled to rt and concentrated to a minimumvolume, then purified directly by FCC (0 to 10% 2 M NH₃ in MeOH/CH₂Cl₂).The material obtained (58 mg) was further purified by reversed-phaseHPLC (Dionex conditions) to yield the title compound (10 mg, 11%). MS(ESI): mass calcd. for C₁₄H₂₄N₄, 248.4; m/z found, 249.3 [M+H]⁺. ¹H NMR(CDCl₃): 7.73 (d, J=6.0, 1 H), 5.86 (dd, J=6.1, 2.0, 1H), 5.38 (d,J=2.0, 1 H), 4.70-4.45 (m, 1 H), 3.51 (dd, J=9.8, 6.2, 1H), 3.44 (dd,J=14.7, 8.7, 1H), 3.39-3.29 (m, 2H), 3.10 (dd, J=9.7, 4.9, 1H),3.03-2.97 (m, 2H), 2.48 (s, 3H), 2.20 (dd, J=12.6, 7.6, 1H), 1.96-1.77(m, 2H), 0.99 (d, J=6.7, 7H).

Example 2344(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine

[(3R)-1-(2-Chloro-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester. To a slurry of 2,4-dichloropyrimidine (2.05 g, 13.7mmol) and N,N-diisopropylethylamine (3.60 mL, 20.6 mmol) in i-PrOH (12mL) was added (R)-3-N-Boc-amino pyrrolidine (2.69 g. 14.4 mmol). Themixture was heated at 160° C. in a microwave for 2 h. The reaction wascooled to rt and concentrated, and the crude residue was purified by FCC(0 to 50% EtOAc/hexanes) to yield a white solid (2.10 g, 51%). MS (ESI):mass calcd. for C₁₃H₁₉CIN₄O₂, 298.1; m/z found, 299.1 [M-F1-1]⁺. ¹H NMR(CDCl₃): 8.02 (d, J=6.0, 1H), 6.19 (d, J=6.0, 1H), 4.85-4.47 (m, 1H),4.40-4.16 (m, 1H), 3.94-3.08 (m, 4H), 2.46-2.17 (m, 1H), 2.12-1.78 (m,1H), 1.45 (s, 9H).

[(3R)-1-(2-Isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester. To a slurry of[(3R)-1-(2-chloro-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (103 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.09mL, 0.52 mmol) in i-PrOH (1.5 mL) was added bisobutylamine (30 mg. 0.41mmol). The mixture was heated to 140° C. in a microwave for 6 h. Thereaction was cooled to room temperature and concentrated. The cruderesidue was purified by FCC (0 to 10% MeOH/CH₂Cl₂) to yield the desiredproduct (93 mg, 80%). MS (ESI): mass calcd. for C₁₇H₂₉N₅O₂, 335.2; m/zfound, 336.3 [M-F1-1]⁺. ¹H NMR (CDCl₃): 7.83 (d, J=5.9, 1 H), 5.64 (d,J=5.9, 1H), 4.98-4.80 (m, 1H), 4.78-4.61 (m, 1H), 4.38-4.20 (m, 1H),3.79-3.26 (m, 4H), 3.23-3.11 (m, 2H), 2.32-2.09 (m, 1H), 1.99-1.77 (m,2H), 1.45 (s, 9H), 0.95 (d, J=6.7, 6H).

4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine. Toa solution of[(3R)-1-(2-isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (93 mg, 0.28 mmol) in MeOH (0.5 mL) was added HCl (4.0M in 1,4-dioxane; 1.0 mL). The reaction was stirred at rt for 2 h,concentrated, and the crude residue was purified by FCC (0 to 20% 2 MNH₃ in MeOH/CH₂Cl₂) to yield the desired product (65 mg, 100%). MS(ESI): mass calcd. for C₁₂H₂₁ N₅, 235.2; m/z found, 236.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.82 (d, J=5.9, 1 H), 5.65 (d, J=5.9, 1H), 4.87 (s, 1H),3.75-3.51 (m, 3H), 3.48-3.38 (m, 1H), 3.20 (dd, J=6.7, 6.1, 3H), 2.16(d, J=6.3, 1H), 1.87 (dt, J=13.4, 6.7, 1H), 1.81-1.71 (m, 1H), 1.47 (s,2H), 0.95 (d, J=6.7, 6H).

The compounds in Example 24 through Example 30 were prepared usingmethods analogous to those described for Example 23.

Example 244-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopropylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.83 (d, J=5.9, 1H), 5.66 (d, J=5.9, 1H), 4.89 (s, 1H),3.76-3.37 (m, 4H), 3.23 (dd, J=7.0, 5.6, 2H), 3.20-3.11 (m, 1H),2.21-2.10 (m, 1H), 1.82-1.70 (m, 1H), 1.40 (s, 2H), 1.16-0.97 (m, 1H),0.59-0.39 (m, 2H), 0.32-0.14 (m, 2H).

Example 254-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.83 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.74 (d, J=6.6,1H), 4.33-4.11 (m, 1H), 3.80-2.93 (m, 5H), 2.22-2.10 (m, 1H), 2.08-1.96(m, 2H), 1.82-1.54 (m, 5H), 1.51-1.17 (m, 4H).

Example 264-[(3R)-3-Aminopyrrolidin-1-A-N-(2,2-dimethylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.2; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.96-4.66 (m,1H), 3.80-3.33 (m, 4H), 3.23 (d, J=6.4, 2H), 3.20-3.08 (m, 1H),2.27-2.04 (m, J =6.2, 1 H), 1.85-1.63 (m, 1H), 1.26 (s, 2H), 0.95 (s,9H).

Example 271-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2-methylpropan-2-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2; m/z found, 252.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.79 (d, J=6.0, 1H), 5.93 (br s, 1H), 5.69 (d, J=6.0, 1H),5.23 (s, 1H), 3.77-3.30 (m, 6H), 3.28-2.93 (m, 1H), 2.24-2.05 (m, 1H),1.86-1.71 (m, 1H), 1.66-1.33 (m, 2H), 1.23 (s, 6H).

Example 28 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclobutylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 5.00-4.83 (m,1H), 4.51-4.35 (m, 1H), 3.76-3.32 (m, 4H), 3.25-2.96 (m, 1H), 2.47-2.30(m, 2H), 2.23-2.06 (m, 1H), 1.94-1.60 (m, 5H), 1.57-1.31 (m, 2H).

Example 294-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 249.2; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.83 (d, J=5.9, 1H), 5.69 (d, J=5.9, 1H), 4.98-4.84 (m,1H), 4.61-4.47 (m, 1H), 4.05-3.88 (m, 2H), 3.88-3.77 (m, 1H), 3.73-3.32(m, 5H), 3.26-3.02 (m, 1H), 2.35-2.22 (m, 1H), 2.20-2.10 (m, 1H),1.92-1.69 (m, 2H), 1.54-1.16 (m, 2H).

Example 304-[(3R)-3-Aminopyrrolidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.2; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.83 (d, J=5.9, 1H), 5.68 (d, J=5.9, 1H), 4.71 (d, J=7.5,1H), 4.09-3.84 (m, 3H), 3.75-3.34 (m, 6H), 3.26-2.99 (m, 1H), 2.24-2.09(m, 1H), 2.03 (d, J=12.3, 2H), 1.86-1.69 (m, 1H), 1.60-1.19 (m, 4H).

Example 31 Isobutyl44-(4-methyl-piperazin-1-yl)-pyrimidin-2-yl]amine

(4-Chloro-pyrimidin-2-yl)-isobutyl-amine and(2-Chloro-pyrimidin-4-yl)-isobutyl-amine. To a slurry of2,4-dichloropyrimidine (1.48 g, 10.0 mmol) and N,N-diisopropylethylamine(2.60 mL, 15.0 mmol) in i-PrOH (8 mL) was added isobutylamine (0.77 g.10.5 mmol). The mixture was heated at 160° C. in a microwave for 1 h.The mixture was cooled to rt and concentrated to provide a mixture ofregioisomers. (4-Chloro-pyrimidin-2-yl)-isobutyl-amine. MS (ESI): masscalcd. for C₈H₁₂CIN₃, 185.1; m/z found, 186.1 [M+H]⁺. ¹H NMR (CDCl₃):8.13 (s, 1H), 6.53 (d, J=5.2, 1H), 5.43 (s, 1H), 3.25 (dd, J=6.9, 6.0,2H), 1.98-1.79 (m, 1H), 0.97 (d, J=6.7, 6H).(2-Chloro-pyrimidin-4-yl)-isobutyl-amine. MS (ESI): mass calcd. forC₈H₁₂CIN₃, 185.1; m/z found, 186.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.19-7.75 (m,1H), 6.69-6.18 (m, 2H), 3.40-2.98 (m, 2H), 1.98-1.83 (m, 1H), 0.96 (d,J=6.6, 6H).

Isobutyl44-(4-methyl-piperazin-1-yl)-pyrimidin-2-yl]-amine. To a slurryof an unmeasured portion of the mixture from the previous step (60 mg,0.32 mmol) in i-PrOH (2.0 mL) was added 1-methylpiperazine (80 mg, 0.80mmol). The mixture was heated at 160° C. in a microwave for 1 h. Themixture was cooled to rt and concentrated, and the crude residue waspurified by preparatory TLC (7% 2 M NH₃ in MeOH/CH₂Cl₂) to yield thedesired product (12 mg). MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.2; m/zfound, 250.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.87 (d, J=6.0, 1H), 5.85 (d,J=6.1, 1 H), 4.87 (s, 1H), 3.70-3.51(m, 4H), 3.19 (dd, J=6.7, 6.0, 2H),2.52-2.38 (m, 4H), 2.33 (s, 3H), 1.92-1.79 (m, 1H), 0.96 (d, J=6.7, 6H).

Example 32 was prepared using methods analogous to Example 31.

Example 324-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.2; m/z found, 250.3 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.86 (s, 1H),3.79-3.26 (m, 4H), 3.24-3.15 (m, 3H), 2.48 (s, 3H), 2.23-2.09 (m, 1H),1.93-1.74 (m, 3H), 0.95 (d, J=6.7, 6H).

The compounds in Example 33 through Example 42 were prepared usingmethods analogous to those described for Example 1 or Example 16.

Example 334-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-phenylpyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2 m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.94 (d, J=6.1, 1H), 5.83 (d, J=6.1, 1H), 3.67-3.58 (m,4H), 3.57-3.50 (m, 4H), 2.50-2.41 (m, 4H), 2.33 (s, 3H), 2.00-1.84 (m,4H).

Example 34443-(Methylamino)azetidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 268.4 m/z found, 269.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.70 (d, J=6.1, 1H), 7.35-7.28 (m, 2H), 7.28-7.18 (m, 2H),6.92 (tt, J=7.4, 1.3, 1H), 6.08 (dd, J=6.1, 2.2, 1H), 5.95 (d, J=2.1,1H), 3.49 (dd, J=10.0, 6.4, 1 H), 3.46-3.37 (m, 1H), 3.37-3.24 (m, 3H),3.09 (dd, J=10.0, 5.2, 1 H), 2.21 (dq, J=7.7, 5.9, 1H), 1.93-1.80 (m,1H).

Example 35 N-(Cyclopropylmethyl)-4-piperazin-1-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₀N₄, 232.3 m/z found, 233.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.81 (d, J=6.1, 1H), 6.12 (dd, J=6.1, 2.3, 1H), 5.70 (d,J=2.2, 1H), 4.58 (s, 1H), 3.23 (dd, J=6.1, 4.1, 4H), 3.08 (dd, J=6.5,4.4, 2H), 3.02-2.93 (m, 4H), 1.99 (s, 2H), 1.17-0.99 (m, 1H), 0.63-0.39(m, 2H), 0.33-0.10 (m, 2H).

Example 36 N-Butyl-4-piperazin-1-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.3 m/z found, 235.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.61 (d, J=6.3, 1 H), 6.20 (dd, J=6.4, 2.4, 1H), 5.84 (d,J=2.3, 1H), 3.26 (dd, J=6.1, 4.2, 4H), 3.20 (t, J=7.0, 2H), 2.91 (dd,J=6.2, 4.1, 4H), 1.64-1.52 (m, 2H), 1.43 (dq, J=14.2, 7.2, 2H), 0.96(dd, J=9.7, 5.0, 3H).

Example 37 N-(2-Methoxyethyl)-4-piperazin-1-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₀N₄O, 236.3 m/z found, 237.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.63 (d, J=6.3, 1H), 6.23 (dd, J=6.3, 2.3, 1H), 5.91 (d, J=2.3, 1 H), 3.55 (t, J=5.5, 2H), 3.40 (t, J=5.4, 2H), 3.37 (s, 3H),3.28-3.24 (m, 4H), 2.91 (dd, J=6.1, 4.2, 4H).

Example 38 N-Phenyl-4-piperazin-1-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₁₈N₄, 254.3 m/z found, 255.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.89-12.43 (m, 1H), 10.17 (s, 1H), 9.70 (s, 2H), 7.81(d, J=7.5 Hz, 1 H), 7.45 (t, J=7.8, Hz, 2H), 7.31 (d, J=7.7 Hz, 2H),7.24 (t, J=7.3, Hz, 1H), 6.75 (dd, J=7.4, 2.1 Hz, 1H), 6.35 (d, J=2.0Hz, 1H), 3.75 (s, 4H), 3.20 (s, 4H).

Example 394-Piperazin-1-yl-N-(tetrahydrofuran-2-ylmethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₂N₄O, 262.4 m/z found, 263.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=6.1, 1H), 6.13 (dd, J=6.1, 2.3, 1H), 5.76 (d, J=2.2, 1 H), 4.65 (s, 1H), 4.09 (qd, J=7.0, 4.0, 1 H), 3.88 (dt, J=8.2,6.7, 1H), 3.77 (dd, J=14.4, 7.6, 1H), 3.52 (ddd, J=13.0, 6.5, 4.0, 1H),3.26 (dd, J =7.2, 5.1, 1H), 3.22 (dd, J=6.1, 4.0, 4H), 2.97 (dd, J=6.1,4.1, 4H), 2.61 (s, 1H), 2.06-1.96 (m, 1H), 1.96-1.85 (m, 2H), 1.79 (s,2H), 1.72-1.60 (m, 1H).

Example 40 N-(4-Fluorobenzyl)-4-piperazin-1-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₁₉FN₄, 286.4 m/z found, 287.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.84 (d, J=6.1, 1H), 7.39-7.29 (m, 2H), 7.08-6.93 (m, 2H),6.16 (dd, J=6.1, 2.3, 1H), 5.68 (d, J=2.2, 1H), 4.68 (s, 1H), 4.44 (d,J=5.6, 2H), 3.18 (dd, J=6.2, 4.1, 4H), 2.95 (dd, J=6.2, 4.1, 4H).

Example 41N-(2,2-Dimethylpropyl)-44(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₆N₄O, 262.4 m/z found, 263.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.30 (s, 1 H), 9.39 (br s, 2H), 7.70-7.60 (m, 2H), 6.26(dd, J=7.4, 2.2, 1H), 5.79 (s, 1H), 3.89 (s, 1H), 3.81-3.3.62 (m, 3H),3.53 (br s, 1H), 3.08 (d, J=6.0, 2H), 2.61 (s, 3H), 2.43-2.21 (m, 2H),0.96 (s, 9H).

Example 42N-(2-Methoxyethyl)-44(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.4 m/z found, 251.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.13 (s, 1H), 9.53 (s, 1H), 9.41 (s, 1H), 7.70-7.60 (m,2H), 6.29 (dd, J=7.4, 2.2, 1H), 5.75 (s, 1H), 3.89 (s, 1H), 3.85-3.62(m, 4H), 3.50 (t, J=4.8, 2H), 3.44 (t, J=5.5, 2H), 3.29 (s, 3H), 2.60(s, 3H), 2.45-2.33 (m, 2H).

The compounds in Example 43 through Example 83 were prepared usingmethods analogous to those described for Example 23.

Example 434-[(3R)-3-Aminopyrrolidin-1-yl]-N-[bicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₃N₆, 273.4 m/z found, 274.2 [M+H]. ¹H NMR(D₂O): 8.69-8.29 (m, 1H), 7.64 (s, 1H), 6.14 (s, 1H), 4.25-3.52 (m, 6H),2.63-2.12 (m, 4H), 1.96-1.74 (m, 1H), 1.65-1.04 (m, 8H).

Example 44N-[Bicyclo[2.2.1]hept-2-yl]-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₆N₆, 287.41 m/z found, 288.2 [M+H]. ¹HNMR (CDCl₃): 7.87 (d, J=6.0, 1H), 5.84 (d, J=6.1, 1H), 4.69 (d, J=6.5,1H), 3.75-3.67 (m, 1H), 3.63-3.52 (m, 4H), 2.48-2.39 (m, 4H), 2.32 (s,3H), 2.29-2.22 (m, 2H), 1.86-1.75 (m, 1 H), 1.56-1.38 (m, 3H), 1.30-1.09(m, 4H).

Example 45N-(Cyclopropylmethyl)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.4 m/z found, 248.2 [M+H]. ¹H NMR(D₂O): 7.88 (d, J=6.1, 1 H), 5.86 (d, J=6.1, 1H), 4.93 (s, 1H),3.65-3.55 (m, 4H), 3.22 (dd, J=7.0, 5.5, 2H), 2.47-2.41 (m, 4H), 2.32(s, 3H), 1.11-0.99 (m, 1H), 0.53-0.46 (m, 2H), 0.25-0.18 (m, 2H).

Example 46 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.3 m/z found, 236.2 [M+H]. ¹H NMR(CDCl₃): 7.83 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.75 (s, 1 H),3.75-3.00 (m, 7H), 2.23-2.07 (m, 1H), 1.85-1.67 (m, 1H), 1.64-1.28 (m,6H), 0.94 (t, J=7.3, 3H).

Example 47 N-Butyl-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.4 m/z found, 250.2 [M+H]. ¹H NMR(CDCl₃): 7.87 (d, J=6.0, 1H), 5.85 (d, J=6.1, 1H), 4.78 (s, 1 H),3.65-3.53 (m, 4H), 3.41-3.28 (m, 2H), 2.47-2.40 (m, 4H), 2.32 (s, 3H),1.63-1.48 (m, 2H), 1.45-1.31 (m, 2H), 0.94 (t, J=7.3, 3H).

Example 48 N-Cyclopentyl-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.4 m/z found, 262.2 [M+H]. ¹H NMR(CDCl₃): 7.87 (d, J=6.1, 1H), 5.85 (d, J=6.1, 1H), 4.79 (d, J=6.6, 1H),4.28-4.13 (m, 1H), 3.70-3.51 (m, 4H), 2.48-2.38 (m, 4H), 2.32 (s, 3H),2.07-1.94 (m, 2H), 1.77-1.53 (m, 4H), 1.51-1.37 (m, 2H).

Example 49N-(2,2-DimethylpropyI)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.4 m/z found, 264.2 [M+H]. ¹H NMR(CDCl₃): 7.86 (d, J=6.0, 1H), 5.84 (d, J=6.1, 1H), 4.84 (s, 1H),3.67-3.53 (m, 4H), 3.21 (d, J=6.3, 2H), 2.51-2.38 (m, 4H), 2.30 (s, 3H),0.95 (s, 9H).

Example 504-(4-Methylpiperazin-1-yl)-N-(tetrahydrofuran-2-ylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.4 m/z found, 278.2 [M+H]. ¹HNMR (CDCl₃): 7.87 (d, J=6.1, 1H), 5.86 (d, J=6.1, 1H), 5.07 (s, 1H),4.11-4.01 (m, 1H), 3.92-3.84 (m, 1 H), 3.79-3.71 (m, 1 H), 3.63-3.51 (m,5H), 3.47-3.36 (m, 1H), 2.47-2.39 (m, 4H), 2.32 (s, 3H), 2.03-1.83 (m,3H), 1.69-1.58 (m, 1H).

Example 514-[(3R)-3-Aminopyrrolidin-1-yl]-N-(tetrahydrofuran-2-ylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.4 m/z found, 264.2 [M+H]. ¹HNMR (D₂O): 8.74-8.23 (m, 1H), 7.65 (d, J=7.2, 1H), 6.16 (s, 1H),4.28-3.41 (m, 11H), 2.64-2.41 (m, 1H), 2.37-2.15 (m, 1H), 2.12-1.83 (m,4H), 1.76-1.59 (m, 1H).

Example 524-[(3R)-3-Aminopyrrolidin-1-yl]-N-(1-methylethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.3 m/z found, 222.2 [M+H]. ¹H NMR(D₂O): 8.64-8.31 (m, 1H), 7.62 (d, J=7.3, 1 H), 6.14 (d, J=6.3, 1 H),4.24-3.59 (m, 6H), 2.65-2.40 (m, 1H), 2.37-2.11 (m, 1H), 1.23 (d, J=6.5,6H).

Example 53 N-(1-Methylethyl)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.3 m/z found, 236.2 [M+H]. ¹H NMR(CDCl₃): 7.87 (d, J=6.1, 1H), 5.84 (d, J=6.1, 1H), 4.63 (d, J=7.4, 1H),4.16-4.00 (m, 1H), 3.66-3.50 (m, 4H), 2.49-2.39 (m, 4H), 2.32 (s, 3H),1.21 (d, J=6.5, 6H).

Example 54 N-Cyclobutyl-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.4 m/z found, 248.2 [M+H]. ¹H NMR(CDCl₃): 7.86 (d, J=6.1, 1H), 5.85 (d, J=6.1, 1H), 4.99 (d, J=7.0, 1H),4.46-4.35 (m, 1H), 3.65-3.53 (m, 4H), 2.47-2.34 (m, 6H), 2.32 (s, 3H),1.93-1.80 (m, 2H), 1.77-1.63 (m, 2H).

Example 554-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopropylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.3 m/z found, 220.2 [M+H]. ¹H NMR(D₂O): 8.64-8.30 (m, 1H), 7.71 (d, J=7.3, 1 H), 6.23 (d, J=7.3, 1 H),4.22-4.02 (m, 1H), 4.00-3.88 (m, 1 H), 3.85-3.59 (m, 3H), 2.76-2.59 (m,1H), 2.56-2.38 (m, 1H), 2.32-2.11 (m, 1H), 0.98-0.80 (m, 2H), 0.72-0.58(m, 2H).

Example 56 N-Cyclopropyl-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.3 m/z found, 234.2 [M+H]. ¹H NMR(CDCl₃): 7.93 (d, J=6.1, 1H), 5.91 (d, J=6.1, 1H), 5.02 (s, 1H),3.65-3.55 (m, 4H), 2.78-2.68 (m, 1H), 2.48-2.39 (m, 4H), 2.32 (s, 3H),0.79-0.70 (m, 2H), 0.54-0.47 (m, 2H).

Example 574-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₈FN₅, 287.3 m/z found, 288.2 [M+H]. ¹HNMR (D₂O): 8.65-8.24 (m, 1H), 7.65 (d, J=7.1, 1H), 7.48-7.30 (m, 2H),7.19-7.01 (m, 2H), 6.14 (d, J=7.0, 1H), 4.58 (s, 2H), 4.22-4.02 (m, 1H),3.97-3.58 (m, 4H), 2.62-2.36 (m, 1 H), 2.31-2.11 (m, 1 H).

Example 58N-(4-Fluorobenzyl)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₀FN₅, 301.4 m/z found, 302.2 [M+H]. ¹HNMR (CDCl₃): 7.85 (d, J=6.1, 1H), 7.34-7.26 (m, 2H), 7.03-6.92 (m, 2H),5.88 (d, J=6.1, 1H), 5.30 (s, 1H), 4.54 (d, J=5.9, 2H), 3.61-3.53 (m,4H), 2.45-2.37 (m, 4H), 2.31 (s, 3H).

Example 594-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.3 m/z found, 238.2 [M+H]. ¹HNMR (CDCl₃): 7.83 (d, J=5.9, 1H), 5.67 (d, J=5.9, 1H), 5.06 (s, 1 H),3.79-3.39 (m, 8H), 3.37 (s, 3H), 3.24-3.00 (m, 1H), 2.26-2.05 (m, 1H),1.84-1.69 (m, 1H), 1.65-1.21 (m, 2H).

Example 60N-(2-Methoxyethyl)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.3 m/z found, 252.2 [M+H]. ¹HNMR (CDCl₃): 7.88 (d, J=6.1, 1H), 5.87 (d, J=6.1, 1H), 5.09 (s, 1 H),3.65-3.50 (m, 8H), 3.37 (s, 3H), 2.48-2.39 (m, 4H), 2.32 (s, 3H).

Example 614-[(3R)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.3 m/z found, 271.2 [M+H]. ¹H NMR(CDCl₃): 8.54 (d, J=4.2, 1H), 7.86 (d, J=5.9, 1H), 7.61 (td, J=7.7, 1.8,1H), 7.34 (d, J=7.8, 1H), 7.16-7.10 (m, 1H), 5.72-5.61 (m, 2H), 4.73 (d,J=5.8, 2H), 3.71-3.32 (m, 4H), 3.21-3.04 (m, 1H), 2.20-2.05 (m, 1H),1.80-1.68 (m, 1H), 1.38-1.13 (m, 2H).

Example 624-(4-Methylpiperazin-1-yl)-N-(pyridin-2-ylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.4 m/z found, 285.2 [M+H]. ¹H NMR(CDCl₃): 8.55 (ddd, J=4.8, 1.6, 0.8, 1H), 7.91 (d, J=6.1, 1H), 7.61 (td,J =7.7, 1.8, 1H), 7.33 (d, J=7.8, 1H), 7.17-7.11 (m, 1H), 5.89 (d,J=6.1, 1H), 5.72-5.66 (m, 1H), 4.71 (d, J=5.7, 2H), 3.61-3.53 (m, 4H),2.43-2.37 (m, 4H), 2.31 (s, 3H).

Example 63 Cyclopentyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.3 m/z found, 248.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.89-7.84 (m, 1H), 5.87-5.83 (m, 1H), 4.26-4.18 (m, 1H),3.62-3.52 (m, 4H), 2.95-2.87 (m, 4H), 2.07-1.98 (m, 2H), 1.77-1.67 (m,2H), 1.66-1.58 (m, 2H), 1.51-1.41 (m, 2H).

Example 64 (2,2-Dimethyl-propyl)-(4-piperazin-1-yl-pyrimidin-2-yl)-amine

Method A:

The titled compound was prepared using methods analogous to thosedescribed for Example 23. MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.4 m/zfound, 250.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.92-7.86 (m, 1H), 5.86-5.83 (m,1H), 4.97-4.84 (m, 1H), 3.63-3.55 (m, 4H), 3.53-3.47 (m, 4H), 3.24-3.19(m, 2H), 1.51-1.47 (m, 9H).

Method B:

t-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate.

To a mixture of 2,4-dichloropyrimidine (20 g, 0.135 mol, 1 eq.) andDIPEA (26 g, 0.203 mol, 1.5 eq) in i-PrOH (400 mL) was added tert-butylpiperazine-1-carboxylate (27 g, 0.148 mol, 1.1 eq) by portions at 0° C.,and the resulting reaction was stirred overnight (about 15 hrs) at 10°C. A lot of white solid precipitated and TLC showed that there was stilla little 2,4-dichloropyrimidine. The solid was filtered andrecrystallized from DCM to afford the title product (18 g, 45% yield) asa white solid. ¹H NMR (300 MHz, CDCl₃): 8.08 (d, J=6.2 Hz, 1H), 6.41 (d,J=6.2 Hz, 1H), 3.67 (s, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H). t-butyl4-(2-(neopentylamino)pyrimidin-4-yl)piperazine-1-carboxylate. A solutionof tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (300mg, 1 mmol) 2,2-dimethylpropan-1-amine (131mg, 1.5mmol) and DIPEA (259mg, 2 mmol) in pentan-1-ol (15 mL) was stirred at reflux for 18 hrs. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography (100% ethyl acetate) to afford the desiredproduct. ¹H NMR (300 MHz, CDCl₃): 7.88 (d, J=5.7 Hz, 1 H), 5.84 (d,J=6.3 Hz, 1H), 4.97 (br s, 1H), 3.58 (m, 4H), 3.50 (m, 4H), 3.21 (d,J=6.3 Hz, 2H), 1.48 (s, 9H), 0.96 (s, 9H).

N-neopentyl-4-(piperazin-1-yl)pyrimidin-2-amine dihydrochloride. t-butyl4-(2-(neopentylamino)pyrimidin-4-yl)piperazine-1-carboxylate obtainedfrom the previous stey was dissolved in MeOH (4 mL) and 7N HCl / Et₂Osolution (20 mL) was added. The resulting solution was stirred atambient temperature for 18 hrs. The solvent was concentrated to give thedesired product as a yellow solid (130 mg, 40% yield in two steps). ¹HNMR (300 MHz, CD₃OD): 7.84 (d, J=7.2 Hz, 1H), 6.56 (d, J=7.2 Hz, 1H),4.27 (br s, 2H), 4.02 (br s, 2H), 3.40 (br s, 4H), 3.33 (br s, 2H), 1.01(s, 9H); LC-MS, m/z =250.2 [M+H]⁺, t_(R)=0.8 min; HPLC: 99% (214 nm),98% (254 nm), t_(R)=4.7 min.

Example 65 Isobutyl-(4-piperazin-1-yl-pyrimidin-2-yl)amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.3 m/z found, 236.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.89-7.78 (m, 1H), 6.62-6.52 (m, 1H), 4.13-3.97 (m, 2H),3.44-3.37 (m, 4H), 3.35-3.18 (m, 4H), 2.02-1.89 (m, 1H), 1.04-0.97 (m,6H).

Example 66 Cyclopropylmethyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine

MS (ESI): mass calcd. for C₁₂H₂₁₉N₅, 233.3 m/z found, 234.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.87-7.78 (m, 1H), 6.64-6.53 (m, 1H), 3.46-3.36 (m, 4H),3.35-3.29 (m, 4H), 1.20-1.07 (m, 1H), 0.65-0.53 (m, 2H), 0.37-0.28 (m,2H).

Example 67 Isopropyl-(4-piperazin-1-yl-pyrimidin-2-yl)amine

MS (ESI): mass calcd. for _(C11H19N5,) 221.3 m/z found, 222.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.83-7.77 (m, 1H), 6.59-6.50 (m, 1H), 4.36-3.98 (m, 4H),3.46-3.29 (m, 4H), 1.44-1.36 (m, 1H), 1.31-1.24 (m, 6H).

Example 68 Butyl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine

MS (ESI): mass calcd. for C₁₂H₂₁ N₅, 235.3 m/z found, 236.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.87-7.79 (m, 1H), 6.65-6.53 (m, 1H), 4.38-3.99 (m, 4H),3.55-3.29 (m, 6H), 1.73-1.60 (m, 2H), 1.50-1.40 (m, 2H), 1.03-0.95 (m,3H).

Example 69(R)-(4-Piperazin-1-yl-pyrimidin-2-yl)-(-tetrahydro-furan-2-ylmethyl)-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.3 m/z found, 264.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.86-7.79 (m, 1H), 5.86-5.82 (m, 1H), 5.21-5.09 (m, 1H),4.11-4.01 (m, 1H), 3.91-3.80 (m, 1H), 3.78-3.70 (m, 1H), 3.59-3.49 (m,4H), 3.41-3.34 (m, 1H), 2.91-2.84 (m, 4H), 2.45-2.11 (m, 2H), 2.03-1.81(m, 4H), 1.68-1.56 (m, 1H).

Example 70Bicyclo[2.2.1]hept-2-yl-(4-piperazin-1-yl-pyrimidin-2-yl)-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.4 m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.93-7.82 (m, 1H), 5.87-5.81 (m, 1H), 4.99-4.74 (m, 1H),3.75-3.67 (m, 1H), 3.62-3.54 (m, 4H), 3.52-3.44 (m, 4H), 2.30-2.22 (m,2H), 1.85-1.77 (m, 1H), 1.59-1.51 (m, 1H), 1.46-1.40 (m, 1.6H),1.29-1.20 (m, 2.4H), 1.19-1.11 (m, 2H).

Example 71(4-Piperazin-1-yl-pyrimidin-2-yl)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.5 m/z found, 316.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.54-7.41 (m, 1H), 6.25-6.14 (m, 1H), 4.33-4.12 (m, 1H),4.10-3.91 (m, 2H), 3.88-3.62 (m, 2H), 3.29-3.13 (m, 4H), 2.52-2.37 (m,1H), 2.32-2.19 (m, 1H), 1.91-1.73 (m, 2H), 1.72-1.63 (m, 1H), 1.53-1.41(m, 1H), 1.02 (s, 3H), 0.94-0.88 (m, 3H), 0.85 (s, 3H), 0.77-0.71 (m,2H).

Example 72 N-(2-Methoxyethyl)-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.3 m/z found, 238.3 [M+H]⁺. ¹HNMR (CD₃OD): 7.84 (d, 1 H, J=7.4), 6.59 (d, 1H, J=7.3), 4.29 (bs, 2H),4.04 (bs, 2H), 3.59-3.67 (m, 4H), 3.35-3.45 (m, 7H).

Example 73Butyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.2 m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.90 (s, 1H),3.77-3.08 (m, 7H), 2.46 (s, 3H), 2.14 (td, J=13.1, 6.1, 1H), 1.81 (d,J=6.1, 1H), 1.67-1.29 (m, 5H), 0.93 (t, J=7.3, 3H).

Example 74Bicyclo[2.2.1]hept-2-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.2 m/z found, 288.2 [M+H]. ¹H NMR(CDCl₃): 7.76 (d, J=5.8, 1H), 5.60 (d, J=5.9, 1H), 5.12-4.88 (m, 1H),3.69 (s, 2H), 3.29 (s, 2H), 2.61-1.98 (m, 6H), 1.95-0.92 (m, 12H).

Example 75Cyclopentyl44-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2 m/z found, 262.2 [M+H]. ¹H NMR(CDCl₃): 7.75 (d, J=5.9, 1H), 5.58 (d, J=5.9, 1H), 4.97 (s, 1H), 4.17(dd, J =13.6, 6.8, 1H), 3.53 (s, 1H), 3.25 (s, 3H), 2.40 (s, 3H),2.18-1.28 (m, 12H).

Example 76(2,2-Dimethyl-propyl)-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.2 m/z found, 264.2 [M+H]. ¹H NMR(CDCl₃): 7.77 (d, J=5.8, 1H), 5.59 (d, J=5.9, 1H), 4.92 (s, 1H), 3.56(s, 1H), 3.22-3.15 (m, 5H), 2.43 (s, 3H), 2.11 (d, J=6.0, 1H), 1.78 (s,1H), 1.08-0.73(m, 11H).

Example 77Cyclopropylmethyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2 m/z found, 248.2 [M+H]. ¹H NMR(CDCl₃): 7.61 (d, J=5.9, 1H), 5.44 (d, J=5.9, 1H), 4.87 (s, 1H),3.57-2.78 (m, 7H), 2.46-2.04 (m, 3H), 1.93 (td, J=13.3, 6.0, 1H), 1.60(d, J=6.1, 1H), 1.32-0.60 (m, 2H), 0.38-0.16 (m, 2H), 0.14-0.10 (m, 2H).

Example 78Isopropyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.2 m/z found, 236.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.81 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.82 (d, J=7.3,1H), 4.21-4.00 (m, 1H), 3.77-3.08 (m, 5H), 2.67-2.25 (m, 3H), 2.24-1.71(m, 2H), 1.67-0.90 (m, 7H).

Example 79(4-Fluoro-benzyl)44-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₆H₂₀FN₅, 301.2 m/z found, 302.2 [M+H]. ¹HNMR (CDCl₃): 7.76 (d, J=5.7, 1H), 7.40-7.20 (m, 2H), 7.06-6.86 (m, 2H),5.65 (d, J=5.9, 2H), 4.53 (d, J=5.9, 2H), 3.56-3.46 (m, 2H), 3.29 (s,3H), 2.44 (s, 3H), 2.11 (s, 1H), 1.79 (s, 1H), 1.40-1.32 (m, 1H).

Example 80Cyclopropyl44-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2 m/z found, 234.2 [M+H]. ¹H NMR(CDCl₃) 7.89 (d, J=5.9, 1H), 5.71 (d, J=6.0, 1H), 5.13 (s, 1H),3.76-3.11 (m, 5H), 2.82-2.39 (m, 4H), 2.15 (td, J=13.2, 6.0, 1H), 1.82(d, J=6.1, 1H), 1.46 (s, 1H), 0.85-0.64 (m, 2H), 0.60-0.40 (m, 2H).

Example 81[4-(3R)-(3-Methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-(tetrahydro-furan-2-ylmethyl)-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2 m/z found, 278.2 [M+H]. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.66 (d, J=5.9, 1H), 5.11 (s, 1 H),4.15-3.99 (m, 1H), 3.96-3.12 (m, 9H), 2.55 (s, 3H), 2.34-2.05 (m, 1H),2.05-1.56 (m, 6H).

Example 82(2-Methoxy-ethyl)-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-yl]-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2 m/z found, 252.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.82 (d, J=5.9, 1H), 5.66 (d, J=5.9, 1H), 5.17 (s, 1 H),3.79-3.07 (m, 13H), 2.55 (s, 3H), 2.15 (td, J=13.3, 6.0, 1H), 1.82 (d,J=6.1, 1H).

Example 83[4-(3R)-(3-Methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylFpyridin-2-ylmethyl-amine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.2 m/z found, 285.2 [M+H]⁺. ¹HNMR (CDCl₃) 8.46 (d, J=4.8, 1 H), 7.75 (d, J=5.9, 1H), 7.63-7.39 (m,1H), 7.28 (d, J=7.8, 1H), 7.16-6.95 (m, 1H), 6.04 (s, 1H), 5.60 (d,J=5.9, 1 H), 4.66 (d, J=5.8, 2H), 3.49 (s, 2H), 3.40-3.31 (m, 1 H), 3.22(s, 2H), 2.36 (s, 3H), 2.03 (s, 1H), 1.72 (s, 1H), 1.44-1.35 (m, 1H).

Example 84 [4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]butyl-amine

[1-(2-Chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butylester To a flask containing 2,4-dichloropyrimidine (1.6 g, 10.7 mmol)and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in i-PrOH (40 mL) wasadded azetidin-3-yl-carbamic acid tert-butyl ester monohydrochloride(2.1 g. 12.2 mmol). The reaction mixture was heated to 70° C. for 72 h.The reaction was cooled to room temperature, concentrated and the cruderesidue was purified by flash chromatography on SiO₂ (100% hexaneincreasing gradient to 60% EtOAc-Hexane) to yield two isomeric products.The minor upper R_(f) product was obtained as a white solid (326 mg,11%), and the desired major lower R_(f) product was also obtained as awhite solid (2.1 g, 69%).

[1-(2-Butylamino-pyrimidin-4-yl)azetidin-3-yl]-carbamic acid tert-butylester. To a solution of[1-(2-chloro-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butylester (250 mg, 0.778 mmol) in i-PrOH (3.0 mL) was added butylamine (600μL, 6.0 mmol). The reaction mixture was heated to 95° C. in a sealedtube for 36-48 h followed by cooling to room temperature. The reactionmixture was then concentrated and the crude residue purified by flashchromatography on SiO₂ using (100% EtOAc increasing the gradientgradually to 5% 2M NH₃-MeOH) to yield the desired product (260 mg, 92%).

[4-(3-Amino-azetidin-1-yl)-pyrimidin-2-yl]-butyl-amine. To a solution of[1-(2-butylamino-pyrimidin-4-yl)-azetidin-3-yl]-carbamic acid tert-butylester (250 mg, 0.778 mmol) in formic acid (4 mL) was added 6N HCl (300μL). The reaction mixture was stirred at room temperature for 15-30minutes. Then, MeOH (10 mL) was added and stirred for 10 minutes. Thecontents were then concentrated and the crude residue purified by flashchromatography on SiO₂ using an increasing gradient of (0 to 10%NH₃/MeOH in CH₂Cl₂) to yield the desired product (225 mg, 98%) as thefree base. MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.3 m/z found, 222.2[M+H]⁺. ¹H NMR (CD₃OD): 7.61 (d, J=7.3, 1H), 5.99 (d, J=7.1, 1H),4.6-4.7 (m, 2H), 4.28-4.48 (m, 3H), 3.40 (bs, 1H), 1.54-1.62 (m, 2H),1.31-1.41 (m, 2H), 0.90 (t, J=7.4, 3H). The compounds in Example 85through Example 94 were prepared using methods analogous to thosedescribed for Example 84.

Example 85 4-(3-Aminoazetidin-1-yl)-N-cyclopentylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.3 m/z found, 234.2 [M+H]. ¹H NMR(CDCl₃): 7.84 (d, J=6.0, 1H), 5.54 (d, J=5.8, 1H), 4.47 (bs, 1H),4.20-4.28 (m, 3H), 3.90-3.98 (m, 1H), 3.60-3.65 (m, 2H), 1.97-2.06 (m,2H), 1.55-1.75 (m, 6H), 1.39-1.48 (m, 2H).

Example 864-(3-Aminoazetidin-1-yl)-N-(cyclopropylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.3 m/z found, 220.2 [M+H]. ¹H NMR(CDCl₃): 7.62 (d, J=7.3, 1H), 6.00 (d, J=7.3, 1H), 4.6-4.7 (m, 2H),4.28-4.40 (m, 3H), 3.24 (d, J=6.9, 2H), 1.05-1.15 (m, 1H), 0.52-0.59 (m,2H), 0.23-0.30 (m, 2H).

Example 874-(3-Aminoazetidin-1-yl)-N-bicyclo[2.2.1]hept-2-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₁ N₅, 259.4 m/z found, 260.2 [M+H]. ¹HNMR (CDCl₃): 7.60 (d, J=7.2, 1H), 6.00 (d, J=6.8, 1H), 4.55-4.70 (m,2H), 4.25-4.43 (m, 3H), 3.65 (bs, 1H), 2.25-2.35 (m, 2H), 1.80-1.84 (m,1H), 1.32-1.60 (m, 4H), 1.10-1.30 (m, 3H).

Example 884-(3-Aminoazetidin-1-yl)-N-(2,2-dimethylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.3 m/z found, 236.2 [M+H]. ¹H NMR(CDCl₃): 7.61 (d, J=7.2, 1H), 5.99 (d, J=7.1, 1H), 4.58-4.70 (m, 2H),4.28-4.42 (m, 2H), 3.22 (bs, 1H), 0.934 (s, 9H).

Example 89 4-(3-Aminoazetidin-1-yl)-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.3 m/z found, 222.2 [M+H]. ¹H NMR(CDCl₃): 7.61 (d, J=7.3, 1H), 6.00 (d, J=7.0, 1H), 4.59-4.70 (m, 2H),4.29-4.45 (m, 3H), 3.20 (bs, 2H), 1.85-1.94 (m, 1H), 0.92 (d, J=6.7,6H).

Example 90 4-(3-Aminoazetidin-1-yl)-N-(1-methylethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.3 m/z found, 208.2 [M+H]. ¹H NMR(CDCl₃): 7.83 (d, J=5.6, 1H), 5.54 (d, J=5.2, 1H), 4.7 (bs, 1H), 4.24(apparent t, J=7.6 and 8.4, 2H), 4.05-4.15 (m, 1H), 3.90-3.98 (m, 1H),3.60-3.65 (m, 2H), 1.75 (bs, 2H), 1.19 (d, J=6.4, 6H).

Example 91 4-(3-Aminoazetidin-1-yl)-N-cyclopropylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₀H₁₅N₅, 205.3 m/z found, 206.2 [M+H]. ¹H NMR(CDCl₃): 7.69 (d, J=7.3, 1H), 6.01 (d, J=7.3, 1H), 4.55-4.70 (m, 5H),4.25-4.42 (m, 3H), 2.65 (bs, 1H), 0.85-0.95 (m, 2H), 0.66-0.71 (m, 2H).

Example 92 4-(3-Aminoazetidin-1-yl)-N-(4-fluorobenzyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₁₆FN₅, 273.3 m/z found, 274.2 [M+H]. ¹HNMR (CDCl₃): 7.62 (d, J=7.3, 1H), 7.39 (dd, J=5.7, 8.2, 2H), 7.12 (t,J=8.9, 2H), 6.00 (d, J=7.3, 1H), 4.52-4.65 (m, 4H), 4.23-4.40 (m, 3H).

Example 934-(3-Aminoazetidin-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅O, 235.3 m/z found, 236.2 [M+H]. ¹HNMR (CDCl₃): 7.64 (d, J=7.3, 1H), 6.04 (d, J=7.3, 1H), 4.55-4.68 (m,3H), 4.30-4.41 (m, 3H), 3.94-4.10 (m, 2H), 3.85-3.91 (m, 1H), 3.79(apparent dd, J=3.0, 9.6, 1H), 2.30-2.40 (m, 1H), 1.96-2.40 (m, 1H).

Example 944-(3-Aminoazetidin-l-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 249.3 m/z found, 250.2 [M+H]. ¹HNMR (D₂O): 7.63 (d, J=7.31, 1H), 6.02 (d, J=7.29, 1 H), 4.58-4.68 (m,2H), 4.30-4.41 (m, 3H), 4.12-4.20 (m, 1H), 3.75-3.90 (m, 2H), 3.48-3.55(bs, 2H), 1.87-2.10 (m, 3H), 1.16-1.171 (m, 1H).

Example 955-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridazin-3-amine

[1-(6-Chloro-pyridazin-4-yl)-pyrrolidin-3-yl]-methyl-carbamic acidtert-butyl ester. A solution of 3,5-dichloropyridazine (149 mg, 1.0mmol) in THF (3 mL) at 23° C. was treated with(R)-methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (440 mg, 2.2mmol) and the reaction stirred at 23° C. for 18 h. The reaction dilutedwith EtOAc (30 ml) and solution washed with water (2×5 ml) and combinedorganic solution dried and concentrated and crude material purified on16 g SiO₂ (0 to 30% EtOAc: Hex) to yield 283 mg (91% yield) of thedesired regioisomer and 17 mg (5% yield) of the undesired regioisomer.MS (ESI): mass calcd. for C₁₄H₂₁CIN₄O₂, 312.5 m/z found, 313.5 [M+H]⁺.

[1-(6-lsobutylamino-pyridazin-4-yl)-pyrrolidin-3-yl]-methyl-carbamicacid tert-butyl ester. A solution of[1-(6-chloro-pyridazin-4-yl)-pyrrolidin-3-yl]-methyl-carbamic acidtert-butyl ester (32 mg, 0.1 mmol) in isobutylamine (1.0 ml) in a sealedtube was heated to 120° C. for 72 h. The resulting solution was purifieddirectly on 12 g SiO₂ (0 to 5% NH₃/MeOH:CH₂Cl₂) to yield 20 mg (55%yield).

Isobutyl-[5-(3-methylamino-pyrrolidin-1-yl)-pyridazin-3-yl]-aminedihydrochloride. To a stirring solution of[1-(6-isobutylamino-pyridazin-4-yl)-pyrrolidin-3-yl]-methyl-carbamicacid tert-butyl ester (19 mg, 0.06 mmol) in 96% formic acid (0.5 mL) wasadded 0.05 ml of aqueous 6N HCl. The mixture was stirred for 2 hr,diluted with MeOH and concentrated under reduced pressure (repeat 3×) togive the desired product as a white solid (101 mg, >99%). MS (ESI): masscalcd. for C₁₃H₂₃N₅, 249.4 m/z found, 250.2 [M+H]. ¹H NMR (400 MHz,CD₃OD): 8.12 (d, J=2.5, 1H), 6.08 (s, 1H), 4.11-4.01 (m, 1 H), 4.04-3.47(m, 4H), 3.35 (s, 1H), 3.15 (d, J=7.0, 2H), 2.82 (s, 3H), 2.65-2.53 (m,1 H), 2.43-2.31 (m, J=5.6, 1H), 1.96 (dt, J=13.4, 6.7, 1H), 1.03 (d,J=6.7, 6H). The compounds in Example 96 through Example 100 wereprepared using methods analogous to those described for Example 95.

Example 96N-Bicyclo[2.2.1]hept-2-yl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.4 m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.07 (d, J=2.5, 1H), 5.44 (d, J=2.2, 1H), 4.60 (s, 1H),3.51 (dd, J =15.3, 9.3, 2H), 3.40 (dd, J=12.2, 6.6, 3H), 3.14 (dd,J=9.9, 4.5, 1H), 2.49 (s, 3H), 2.29 (d, J=12.1, 2H), 2.21 (dd, J=14.0,6.4, 1H), 1.95-1.79 (m, 2H), 1.49 (dd, J=20.4, 9.0, 4H), 1.33-1.10 (m,5H).

Example 975-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.5 m/z found, 330.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.07 (d, J=2.4, 1H), 5.49 (d, J=2.4, 1H), 4.58 (s, 1H),3.93 (s, 1 H), 3.58-3.44 (m, 3H), 3.44-3.29 (m, 3H), 3.14 (dd, J=9.8,4.6, 1H), 2.67 (s, 1H), 2.49 (s, 3H), 2.40 (s, 1H), 2.21 (dd, J=13.4,7.0, 1H), 1.98 (s, 1H), 1.88 (t, J=13.2, 3H), 1.65 (d, J=14.0, 2H),1.50-1.43 (m, 2H), 1.24 (s, 3H), 1.17 (d, J=7.1, 3H), 1.07 (s, 3H), 0.96(d, J=9.8, 1H).

Example 98N-Cyclohexyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.2 [M+H]⁺. ¹HNMR (D₂O): 7.99 (d, J=2.3, 1H), 5.90 (s, 1H), 4.08 (s, 1 H), 3.76 (s,4H), 3.52 (s, 1H), 2.81 (s, 3H), 2.64-2.49 (m, 1H), 2.34 (d, J=5.8, 1H),1.98 (s, 2H), 1.74 (s, 2H), 1.60 (s, 1H), 1.45-1.13 (m, 5H).

Example 99N-(Cyclopropylmethyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₁ N₅, 247.4 m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.09 (d, J=2.5, 1H), 5.47 (d, J=2.5, 1H), 4.70 (s, 1H),3.56-3.44 (m, 2H), 3.43-3.29 (m, 2H), 3.13 (dd, J=7.0, 5.4, 3H), 2.48(s, 3H), 2.25-2.12 (m, 1H), 1.89 (td, J=13.1, 5.8, 1H), 1.15-1.00 (m,1H), 0.59-0.49 (m, 2H), 0.28-0.22 (m, 2H).

Example 100N-Butyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.4 m/z found, 250.2 [M+H]⁺. ¹HNMR (D₂O): 8.01 (s, 1 H), 5.93 (s, 1 H), 4.09 (s, 1 H), 3.74 (s, 4H),3.31 (dd, J =13.2, 6.2, 2H), 2.81 (s, 3H), 2.59 (d, J=6.8, 1 H), 2.35(s, 1 H), 1.69-1.55 (m, 2H), 1.39 (dd, J=14.9, 7.4, 2H), 0.91 (t, J=7.4,3H).

Example 1015-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridazin-3-amine

3-Chloro-5-(4-methyl-piperazin-1-yl)-pyridazine. A solution of3,5-dichloropyridazine (298 mg, 2.0 mmol) in THF (6 mL) at 23° C. wastreated with N-methyl piperazine (490 μL, 2.2 mmol) and the reactionstirred at 23° C. for 18 h. The reaction diluted with EtOAc (30 ml) andsolution washed with water (2×5 ml), and the aqueous back extracted withchloroform and combined organic solution dried and concentrated andcrude material purified on 12 g SiO₂ (0 to 5% NH₃/MeOH:CH₂Cl₂) to yield267 mg (60% yield) of the desired regioisomer. MS (ESI): mass calcd. forC₉H₁₃CIN₄, 212.5 m/z found, 213.3 [M+H]⁺.

5-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridazin-3-amine. Asolution of 3-chloro-5-(4-methyl-piperazin-1-yl)-pyridazine (103mg, 0.5mmol) in DME was treated with isobutylamine (145 μL, 1.5 mmol), Pd(OAc)₂(23 mg, 0.03 mmol), and BINAP (22 mg, 0.04 mmol) in a sealed tube andheated to 85° C. for 1 h. The reaction was diluted with chloroform (15ml), washed with water (5 ml) and the combined organics dried andconcentrated and purified directly on 12 g SiO₂ (0 to 5%NH₃/MeOH:CH₂Cl₂) to yield 34 mg (28% yield). The HCl salt was preparedby dissolving the product in chloroform and adding 1.0 N HCl (0.3 mL,0.3 mmol) in diethyl ether, and concentrating. MS (ESI): mass calcd. forC₉H₂₀N₆, 249.4 m/z found, 250.2 [M+H]⁺. ¹H NMR (DMSO-d₆): 14.04-13.83(m, 1 H), 11.61-11.35 (m, 1H), 8.46 (s, 2H), 8.33 (s, 1H), 6.51 (s, 1H),4.38-4.16 (m, 2H), 3.64-3.48 (m, 4H), 3.22-3.06 (m, 4H), 2.86-2.73 (m,3H), 1.91-1.78 (m, 1 H), 0.95 (d, J=6.6, 6H).

The compounds in Example 102 through Example 206 were prepared usingmethods analogous to those described in Example 64, Method B.

Example 102N-(Cyclohexylmethyl)-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.2 Hz, 1H), 6.10 (d, J=6.9 Hz, 1H),4.67-4.57 (m, 2H), 4.42-4.28 (m, 3H), 2.79 (s, 3H), 1.80-1.63 (m, 6H),1.39-1.26 (m, 4H), 1.07-1.00 (m, 2H).

Example 1034-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R)-1-cyclohexylethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₇N₅, 289.43 m/z found, 290.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1H), 6.26 (t, J=7.2 Hz, 1H),4.15-3.68 (m, 6H), 2.60-2.48 (m, 1H), 2.32-2.21 (m, 1H), 1.90-1.70 (m,5H), 1.60-1.40 (m, 1H), 1.40-1.30 (m, 3H), 1.25 (d, J=6.6 Hz, 3H),1.20-1.00 (m, 2H).

Example 104N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₁N₅, 341.5 m/z found, 342.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.27 (d, J=7.2 Hz, 1H),4.60-3.92 (m, 5H), 3.74-3.44 (m, 5H), 2.45-2.32 (m, 3H), 2.20-2.00 (m,6H), 1.97-1.60 (m, 1H), 1.32 (s, 3H), 1.13 (s, 3H), 1.00-0.93 (m, 1H).

Example 105N-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.2 Hz, 1H), 6.10 (d, J=7.2 Hz, 1H),4.75-4.57 (m, 2H), 4.42-4.28 (m, 3H), 3.55-3.45 (m, 2H), 2.79 (s, 3H),2.44-2.36 (m, 2H), 2.04-1.96 (m, 5H), 1.60-1.57 (m, 1H), 1.25 (s, 3H),1.12 (s, 3H), 0.99-0.95 (m, 1H).

Example 1064-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.28-6.23 (m, 1H),4.14-3.67 (m, 5H), 3.55-3.45 (m, 2H), 2.59-2.41 (m, 3H), 2.30-2.20 (m,1H), 2.03-1.88 (m, 5H), 1.63-1.58 (m, 1H), 1.25 (s, 3H), 1.12 (s, 3H),0.98-0.88 (m, 1H).

Example 107N-(Cyclohexylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₇N₅, 301.44 m/z found, 302.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.28 (d, J=6.6 Hz, 1H),4.52-3.93 (m, 4H), 3.77-3.38 (m, 6H), 2.44-2.37m, 1H), 2.20-2.00 (m,1H), 1.90-1.60 (m, 6H), 1.35-1.03 (m, 5H).

Example 1084-[-3-(Methylamino)azetidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.35 m/z found, 264.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.2 Hz, 1H), 6.13 (d, J=7.2 Hz, 1H),4.70-4.60 (m, 2H), 4.50-4.28 (m, 3H), 4.20-3.96 (m, 3H), 3.56- 3.52 (m,2H), 2.78 (s, 3H), 2.00-1.90 (m, 2H), 1.66-1.61 (m, 2H).

Example 1094-[(35)-3-Aminopyrrolidin-1-yl]-N-(cyclopropylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD):7.76 (d, J=7.2 Hz, 1H), 6.29-6.25 (m, 1H),4.15-3.70 (m, 5H), 2.59-2.46 (m, 1H), 2.32-2.21 (m, 1H), 1.20-1.16 (m,1H), 0.59 (d, J=7.5 Hz, 2H), 0.33 (d, J=4.8 Hz, 2H).

Example 1101-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2-methylpropan-2-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.79 (d, J=7.2 Hz, 1H), 6.29-6.25 (m, 1H),4.07-3.67 (m, 5H), 3.49-3.48 (m, 2H), 2.59-2.46 (m, 1H), 2.30-2.17 (m,1H), 1.26 (s, 6H).

Example 1114-[(35)-3-Aminopyrrolidin-1-yl]-N-(2,2-dimethylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (d, J=7.5 Hz, 1H), 6.28-6.24 (m, 1H),4.49-3.67 (m, 5H), 2.61-2.47 (m, 1H), 2.30-2.18 (m, 1H), 1.00 (s, 9H).

Example 112 N-Cyclopropyl-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.29 m/z found, 220.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H),4.13 (br s, 2H), 3.90 (br s, 2H), 3.27 (br s, 4H), 2.56 (br s, 1H),1.00-0.70 (m, 2H), 0.58 (br s, 2H).

Example 113N-[(1R)-1-Cyclohexylethyl]-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₇N₅, 289.43 m/z found, 290.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.73 (d, J=7.2 Hz, 1H), 6.09 (d, J=7.2 Hz, 1H),4.67-4.55 (m, 2H), 4.43-4.25 (m, 3H), 4.10-4.00 (m, 1H), 2.78 (s, 3H),1.80-1.68 (m, 5H), 1.60-1.04 (m, 6H), 1.21 (d, J=6.6 Hz, 3H).

Example 1142-Methyl-1-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.80 (d, J=7.5 Hz, 1H), 6.28 (d, J=7.2 Hz, 1H),4.06-3.50 (m, 7H), 2.84 (s, 3H), 2.60-2.55 (m, 1H), 2.50-2.30 (m,1H),1.28 (s, 6H).

Example 115N-[(1R)-1-Cyclohexylethyl]-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.5 Hz, 1H), 6.26 (d, J=7.2 Hz, 1H),4.60-4.40 (m, 2H), 4.20-3.90 (m, 3H), 3.73-3.58 (m, 1H), 3.70-3.60 (m,3H), 2.45-2.33 (m, 1H), 2.20-2.00 (m, 1H), 1.90-1.70 (m, 5H), 1.60-1.40(m, 1H), 1.40-1.30 (m, 3H), 1.25 (d, J=6.6 Hz, 3H), 1.20-1.00 (m, 2H).

Example 1164-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J =7.2 Hz, 1H), 6.28 (br s, 1H),4.62-4.41(m, 1H), 4.18-3.64 (m, 5H), 2.78-2.41 (m, 3H), 2.32-1.75 (m,5H), 1.21 (s, 3H), 1.21-1.08 (m, 7H).

Example 1174-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.2 Hz, 1H), 7.32-7.23 (m, 5H),6.28-6.26 (m, 1H), 4.10-3.71 (m, 7H), 2.97 (t, J=7.2 Hz, 2H), 2.41-2.18(m, 2H).

Example 1184-[(35)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.34 m/z found, 271.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.88-8.86 (m, 1H), 8.65-8.63 (m, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.05 (t, J=6.6 Hz, 1H), 7.91(d, J=7.2 HZ, 1H), 6.41-6.38(m, 1H), 5.11 (s, 2H), 4.12-3.98 (m, 1H), 3.84-3.35 (m, 4H), 2.61-2.38(m, 1H), 2.29-2.08 (m, 1H).

Example 119N-(Cyclopentylmethyl)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.83 (d, J=6.0 Hz, 1H), 6.59 (br s, 1H), 5.15 (m,1H), 4.42 (m, 1H), 3.71-3.27 (m, 8H), 2.99 (s, 3H), 2.22 (m, 1H),1.90-1.60 (m, 6H),1.31 (m, 2H).

Example 1202-Methyl-1-{[4-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino}propan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.87 (d, J=7.2 Hz, 1H), 6.59 (d, J=7.2 Hz, 1H),5.19 (m, 1H), 4.45 (m, 1H), 3.75-3.26 (m, 8H), 2.99 (s, 3H), 1.28 (s,6H).

Example 121N-(Cyclopentylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.5 Hz, 1 H), 6.24 (m, 1H), 4.03-3.37(m, 7H), 2.59 (s, 3H), 2.70-2.50 (m, 1H), 2.30-2.22 (m, 2H), 1.83-1.64(m, 6H), 1.34-1.30 (m, 2H).

Example 1222-Methyl-1-({4-[3-(methylamino)azetidin-1-yl]pyrimidin-2-yl}amino)propan-2-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (d, J=7.2 Hz, 1H), 6.13 (d, J=6.9 Hz, 1H),4.69-4.58 (m, 2H), 4.45-4.30 (m, 3H), 3.55-3.48 (m, 2H), 2.80 (s, 3H),1.22 (s, 6H).

Example 1234-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1H), 6.29-6.26 (m, 1H),4.08-3.50 (m, 7H), 2.60-2.40 (m, 1H), 2.40-2.20 (m, 2H), 1.83-1.65 (m,6H), 1.34-1.32 (m, 2H).

Example 124 N[2-(Methylsulfanyl)ethyl]-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅S, 253.37 m/z found, 254.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.73 (d, J=7.8 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H),4.16 (br s, 2H), 3.92 (br s, 2H), 3.58 (m, 2H), 3.31-3.28 (m, 4H), 2.66(t, J =6.6 Hz, 2H), 2.05 (s, 3H).

Example 1254-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₁N₅, 341.5 m/z found, 342.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.2 Hz, 1H), 6.18 (d, J=7.5 Hz, 1H),4.50-4.30 (m, 2H), 4.10-3.80 (m, 3H), 3.70-3.40 (m, 4H), 2.37-2.27 (m,2H), 2.10-1.20 (m, 7H), 0.98 (s, 3H), 0.90 (s, 3H), 0.85 (s, 3H).

Example 1264-[3-(Methylamino)azetidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.11 (d, J=7.2 Hz, 1H),4.73-4.56 (m, 2H), 4.44-4.29 (m, 3H), 2.80 (s, 3H), 2.50-2.40 (m, 1H),2.00-1.30 (m, 6H), 1.04 (s, 3H), 0.97 (s, 3H), 0.91 (s, 3H).

Example 1274-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (d, J=7.5 Hz, 1H), 6.28-6.24 (m, 1H),4.60-4.40 (m, 1H), 4.16-3.73 (m, 5H), 2.60-2.26 (m, 3H), 1.90-1.74 (m,3H), 1.53-1.30 (m, 3H), 1.13 (s, 3H), 1.00 (s, 3H), 0.92 (s, 3H).

Example 1284-[(35)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.30-6.25 (m, 1H),4.15-3.73 (m, 5H), 3.70-3.59 (m, 4H), 3.39 (s, 3H), 2.59-2.48 (m, 1H),2.31-2.20 (m, 1H).

Example 1294-[(35)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.25 (t, J=6.9 Hz, 1H),4.07-3.68 (m, 6H), 2.59-2.49(m, 1H), 2.31-2.20 (m, 1H), 2.03-2.00 (m,2H), 1.83-1.81 (m, 2H), 1.50-1.31 (m, 6H).

Example 1303-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₆O, 265.36 m/z found, 266.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=7.5 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H),4.08-3.61(m, 5H), 3.50-3.26 (m, 4H), 2.53-2.41 (m, 1H), 2.24-2.14 (m,1H), 0.91 (s, 6H).

Example 131 N-Benzyl-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₁₉N₆, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.57 (br s, 1H), 9.44 (br s, 2H), 8.74 (br s,1H), 7.93 (d, J=7.2 Hz, 1H), 7.34-7.24 (m, 5H), 6.52 (d, J=7.5 Hz, 1H),4.54 (d, J=5.7 Hz, 2H), 3.95 (br s, 4H), 3.13 (br s, 4H).

Example 132 N-(2-Phenylethyl)-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.48 (br s, 1H), 9.58 (br s, 2H), 8.26 (br s,1H), 7.91 (d, J=7.2 Hz, 1H), 7.30-7.18 (m, 5H), 6.50 (d, J=7.2 Hz, 1H),3.97 (br s, 4H), 3.58-3.54 (m, 2H), 3.18 (br s, 4H), 2.82 (t, J=7.2 Hz,2H).

Example 133 N-Bicyclo[2.2.1]hept-2-yl-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 9.43 (br, s, 1 H), 8.48 (d, J=4.8 Hz, 1H), 7.95(br, s, 1 H), 6.54 (d, J=7.2 Hz, 1H), 4.01 (br, s, 5H), 3.70-3.52 (m,4H), 2.27-2.21 (m, 2H), 1.79-1.72 (m, 1H), 1.48-1.16 (m, 7H).

Example 1344-Piperazin-1-yl-N-R1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.80 (d, J=7.5Hz, 1H), 6.54 (d, J=7.2 Hz, 1H),4.42 (br, s, 1H), 4.11 (br, s, 4H), 3.61-3.58 (m, 1H), 3.38-3.03 (m,4H), 2.67 (m, 1H), 2.50-2.48 (m, 1H), 2.05-2.00 (m, 2H), 1.91-1.83(m,2H),1.73-1.66 (m, 1H), 1.25 (s, 3H), 1.16 (d, J=7.2Hz, 3H), 1.07 (s,3H), 1.04-1.00 (m, 1H).

Example 1353-({443-(Methylamino)azetidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=72 Hz, 1H), 6.01 (d, J=7.2 Hz,1H),4.62-4.59 (m, 2H), 4.40-4.26 (m, 3H), 3.67-3.43 (m, 4H), 1.85-1.79(m, 2H).

Example 1362,2-Dimethyl-3-({443-(methylamino)azetidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.2 Hz, 1H), 6.05 (d, J=6.9 Hz, 1H),4.58-4.52 (m, 2H), 4.32-4.22 (m, 3H), 2.73 (s, 3H), 0.90 (s, 6H).

Example 137 3-[(4-Piperazin-1-ylpyrimidin-2-yl)amino]propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.5 Hz, 1H), 6.44 (d, J=7.2 Hz, 1H),4.16 (br s, 2H), 3.89 (br s, 2H), 3.59-3.44 (m, 4H), 3.28-3.25 (m, 4H),1.79-1.71 (m, 2H).

Example 138 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.52 (d, J=7.2 Hz, 1H), 6.05 (br s, 1H), 4.43-4.36(m, 1H), 4.17-3.13 (m, 9H), 2.29-2.22 (m, 1H), 1.99-1.93 (m, 1H),1.91-1.77 (m, 1H), 0.82 (d, J=6.6 Hz, 6H).

Example 139 N-Cyclopentyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=6.0 Hz, 1H), 6.22 (br s, 1H), 4.44-3.43(m, 9H), 2.34 (m, 1H), 2.07 (br s, 3H), 1.77-1.62 (m, 6H).

Example 1404-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(2-methoxyethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.35 m/z found, 264.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.54 (d, J=7.2 Hz, 1H), 6.09-6.06 (m, 1H), 4.43-4.15(m, 2H), 3.91-3.27 (m, 10H), 3.55 (s, 3H), 2.26-2.24 (m, 1H),1.96-1.93(m, 1H).

Example 1414-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-[(1R)-1-phenylethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.42 m/z found, 310.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.63 (d, J=6.9 Hz, 1H), 7.38-7.13 (m, 5H), 6.12(d, J=7.2 Hz, 1H), 5.03 (br s, 1H), 4.37-4.17 (m, 2H), 3.95-3.72 (m,2H), 3.51-3.33 (m, 4H), 2.28-2.19 (m, 1H), 1.98-1.94 (m, 1H), 1.48 (d,J=7.2 Hz, 3H).

Example 142N-(4-Fluorobenzyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₀FN₅, 313.38 m/z found, 314.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.55 (d, J=7.2 Hz, 1H), 7.33-7.29 (m, 2H), 7.05-6.99(m, 2H), 6.08-6.04 (m, 1H), 4.55 (s, 2H), 4.44-4.35 (m, 1H), 4.11-3.32(m, 7H), 2.26-2.24 (m, 1H),1.91(m, 1H).

Example 143 N-Cyclopropyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₁₉N₅, 245.33 m/z found, 246.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.69 (d, J=7.2 Hz, 1H), 6.24 (d, J=7.5 Hz, 1H),4.39-3.79 (m, 4H), 3.60-3.34 (m, 4H), 2.60-2.50 (m, 1H), 2.30-2.22 (m,1H), 2.00-1.90 (m, 1H), 0.84 (m, 2H), 0.57 (br s, 2H).

Example 144: N-(4-Methoxybenzyl)-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅O, 299.38 m/z found, 300.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=7.5 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H),6.81 (d, J=8.4 Hz, 2H), 6.45 (d, J=7.2 Hz, 1H), 4.46 (s, 2H), 4.13 (brs, 2H), 3.89 (br s, 2H), 3.68 (s, 3H), 3.22 (br s, 4H).

Example 145N-Cyclopropyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=7.5 Hz, 1H), 6.28 (d, J=7.5 Hz, 1H),3.97-3.49 (m, 5H), 2.75 (s, 3H), 2.65-2.33 (m, 3H), 0.92-0.85 (m, 2H),0.63 (s, 2H).

Example 1464-[(35)-3-Aminopyrrolidin-1-yl]-N-bicyclo[2.2.1]hept-2-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J =7.2 Hz, 1H), 6.28 (s, 1H), 4.10-3.81(m, 6H), 2.56-2.53 (m, 1H), 2.36-2.20(m, 2H), 1.93-1.86 (m, 1H),1.61-1.24(m, 8H).

Example 147N-Bicyclo[2.2.1]hept-2-yl-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.15 (d, J=7.2 Hz, 1H),4.67-4.31 (m, 5H), 3.60-3.50 (m, 1H), 2.83 (s, 3H), 2.39-2.33 (m, 2H),1.93-1.86 (m, 1H), 1.62-1.49 (m, 4H), 1.35-1.20 (m, 3H).

Example 1483-({4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol

MS (ESI): mass calcd. for C_(i5)H₂₅N₅O, 291.4 m/z found, 292.2 [M+H]⁺.¹H NMR (300 MHz, CD₃OD): 7.72 (d, J=7.5 Hz, 1H), 6.20 (d, J=5.4 Hz, 1H),4.43-4.38 (m, 1H), 4.38-4.24 (m, 1H), 4.00-3.84 (m, 2H), 3.70-3.50 (m,1H), 3.42-3.26 (m, 6H), 2.36-2.26 (m, 1H), 2.04 (br, s, 1H), 0.91 (s,6H).

Example 1494-[(35)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.2 Hz, 1H), 6.28-6.26 (m, 1H),4.15-3.69 (m, 5H), 3.39-3.32 (m, 2H), 2.61-2.46 (m, 1H), 2.29-2.22 (m,2H), 1.82-1.62 (m, 6H), 1.34-1.31 (m, 2H).

Example 1504-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4,4,4-trifluorobutyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₈F₃N₅, 289.31 m/z found, 290.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.31-6.27 (m, 1H),4.08-3.70 (m, 5H), 3.60-3.55 (m, 2H), 2.59-2.47 (m, 1H), 2.34-2.21 (m,3H), 1.97-1.88 (m, 2H).

Example 1513-{[4-(3-Aminoazetidin-1-yl)pyrimidin-2-yl]amino}-2,2-dimethylpropan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.73 (d, J=7.5 Hz, 1H), 6.08 (d,J=6.9 Hz, 1H),4.64-4.59 (m, 2H), 4.35-4.26 (m, 3H), 3.39-3.29 (m, 4H), 0.94 (s, 6H).

Example 1523-({4-[(35)-3-(Methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.65 (d, J=7.2 Hz, 1H), 6.16 (d, J=6.9 Hz, 1H),3.94-3.46 (m, 9H), 2.71 (s, 3H), 2.50-2.40 (m, 1H), 2.27-2.15 (m, 1H),1.80-1.71 (m, 2H).

Example 1533-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.73 (d, J=7.5 Hz, 1H), 6.08 (d, J=6.9 Hz,1H),4.64-4.59 (m, 2H), 4.35-4.26 (m, 3H), 3.39-3.29 (m, 4H), 0.94 (s,6H).

Example 1543-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.73 (d, J=7.5 Hz, 1H), 6.26 (d, J=6.9 Hz, 1H),4.05-3.54 (m, 9H), 2.65-2.40 (m, 1H), 2.38-2.05 (m, 1H), 1.90-1.81 (m,2H).

Example 155 3-{[4-(3-Aminoazetidin-1-yl)pyrimidin-2-yl]amino}propan-1-ol

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.28 m/z found, 224.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.2 Hz, 1H), 6.09 (d, J=6.6 Hz, 1H),4.62-4.60 (m, 2H), 4.33-4.26 (m, 3H), 3.65 (t, J=6.3 Hz, 2H), 3.51 (br,s, 2H), 1.85-1.79 (m, 2H).

Example 156 N-(4-MethylbenzyI)-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.81 (d, J=7.2 Hz, 1H), 7.25-7.15 (m, 4H), 6.54(d, J=7.5 Hz, 1H), 4.57 (s, 2H), 4.19 (br, s, 2H), 3.96 (br, s, 2H),3.31-3.29 (m, 4H), 2.31 (s, 3H).

Example 157 4-Piperazin-1-yl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.34 m/z found, 271.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.82 (d, J=5.7 Hz, 1H), 8.62 (t, J=7.5 Hz, 1H),8.14 (d, J=7.5 Hz, 1H), 8.02 (t, J=6.6 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H),6.65 (d, J=7.5 Hz, 1H), 5.12 (s, 2H), 3.99 (br, s, 4H).

Example 1582,2-Dimethyl-3-({4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.39 m/z found, 280.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.2 Hz, 1 H), 6.22(s, 1H), 3.99-3.96(m, 3H), 3.88-3.68 (m, 2H), 3.43-3.26 (m, 4H), 2.76 (s, 3H), 2.57-2.31(m, 2H), 0.95 (m, 6H).

Example 1593-({4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.35 m/z found, 264.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.64 (d, J=7.5 Hz, 1H), 6.15 (d, J=7.2 Hz, 1H),4.41-4.17 (m, 2H), 4.01-3.79 (m, 2H), 3.65-3.28 (m, 8H), 2.30-2.23 (m,1H), 2.00-1.95 (m, 1H), 1.78-1.74 (m, 2H).

Example 1604-[(35)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.35 m/z found, 248.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.46 (d, J =7.2 Hz, 1H), 5.99 (d, J=8.7Hz, 1H),4.01-3.96 (m, 2H), 3.81-3.57 (m, 4H), 2.40-2.36 (m, 1H), 2.14-2.08 (m,1H), 1.84-1.78 (m, 2H), 1.54-1.44 (m, 6H).

Example 1613-{[4-(4-Methylpiperazin-1-yl)pyrimidin-2-yl]amino}propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=7.5 Hz, 1H), 6.46 (d, J=7.5 Hz, 1H),3.59-3.47 (m, 8H), 3.27-3.20 (m, 4H), 2.88 (s, 3H), 1.79-1.71 (m, 2H).

Example 162N-Bicyclo[2.2.1]hept-2-yl-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=6.6 Hz, 1H), 6.31 (br s, 1H), 4.05-3.63(m, 6H), 2.85 (s, 3H), 2.61-2.37 (m, 4H), 1.89-1.21 (m, 8H).

Example 163N-(4-MethylbenzyI)-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₆, 297.41 m/z found, 298.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 8.76 (s, 1H), 8.00 (d, J=6.9 Hz, 1H), 7.28 (d,J=7.8 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 6.58 (d, J=6.9 Hz, 1H), 4.55 (d,J=5.4 Hz, 2H), 3.60-3.00 (m, 4H), 2.79 (s, 3H), 2.60-2.40 (m, 4H), 2.31(s, 3H).

Example 1644-(4-Methylpiperazin-1-yl)-N42-(methylsulfanypethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁NS, 267.4 m/z found, 268.1 [M+H]⁺. Amine¹H NMR (300 MHz, CDCl₃): 7.87 (d, J=6.0 Hz, 1 H), 5.89 (d, J=6.0 Hz,1H), 5.25 (s, 1H), 3.61-3.55 (m, 6H), 2.73 (t, J=6.6 Hz, 2H), 2.46-2.43(m, 4H), 2.33 (s, 3H), 2.14 (s, 3H) Salt ¹H NMR (300 MHz, CD₃OD): 7.87(d, J=7.5 Hz, 1H), 6.60 (d, J=7.5 Hz, 1H), 3.00 (s, 3H), 2.80 (t, J=6.6Hz, 3H), 2.18 (s, 3H).

Example 165 N-Benzyl-4-(4-methylpiperazin-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.0 [M+H]⁺.Amine ¹H NMR (300 MHz, CDCl₃): 7.89 (d, J=6.3 Hz, 1H), 7.36-7.24 (m,5H), 5.90 (d, J=6.0 Hz, 1H), 5.19 (br s, 1H), 4.59 (d, J=5.7 Hz, 2H),3.59-3.57 (m, 4H), 2.44-2.41 (m, 4H), 2.32 (s, 3H) Salt ¹H NMR (300 MHz,CD₃OD): 7.88 (d, J=6.6 Hz, 1H), 7.40-7.34 (m, 5H), 6.61 (d, J=6.0 Hz,1H), 5.07-4.43 (m, 4H), 4.67 (s, 2H), 3.66-3.11 (m, 4H), 2.99 (s, 3H).

Example 1662,2-Dimethyl-3-[(4-piperazin-1-ylpyrimidin-2-yl)amino]propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.81 (d, J=7.5 Hz, 1H), 6.53 (d, J=6.9 Hz, 1H),4.26 (br, s, 2H), 4.00 (br, s, 2H), 3.42-3.29 (m, 8H), 0.95 (s, 6H).

Example 1673-({4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, [M+H]⁺. ¹H NMR(300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1 H), 6.28 (d, J=7.5 Hz, 1 H),4.09-3.57 (m, 9H), 2.83 (s, 3H), 2.62-2.55 (m, 1 H), 2.50-2.30 (m, 1 H),1.92-1.83 (m, 2H).

Example 1684-(4-Methylpiperazin-1-yl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.85 (d, J=7.5 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H),4.86-4.80 (m, 2H), 4.60-4.40 (m, 2H), 3.80-3.20 (m, 5H), 3.04 (s, 3H),2.78-2.54 (m, 2H), 2.13-1.74 (m, 4H), 1.35 (s, 3H), 1.23 (d, J=7.2Hz,3H), 1.15 (s, 3H), 1.20-1.07 (m, 1H).

Example 1692,2-Dimethyl-3-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.39 m/z found, 280.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H),4.04-3.73 (m, 5H), 3.43-3.30 (m, 4H), 2.80 (s, 3H), 2.59-2.36 (m, 2H),0.95 (s, 6H).

Example 1704-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(4-methylbenzyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (s, br, 1 H), 7.28 (s, br, 2H), 7.21 (s, br,2H), 6.29 (s, br, 1H), 4.62 (s, 2H), 4.03-3.69 (m, 5H), 2.82 (s, 3H),2.58 (m, 1H), 2.38(m, 1H), 2.35 (s, 3H).

Example 171443-(Methylamino)azetidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.33 m/z found, 236.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.72 (d, J=7.2 Hz, 1H), 6.09 (br s, 1H), 4.62-4.27(m, 5H), 2.77 (s, 3H), 1.95-1.90 (m, 1H), 0.97 (d, J=6.3 Hz, 6H) D20:7.53 (d, J=7.2 Hz, 1H), 5.91 (br s, 1H), 4.60-4.50 (m, 2H), 4.32-4.21(m, 3H), 3.12 (br s, 2H), 2.69 (s, 3H), 1.83-1.79 (m, 1H), 0.83 (d,J=6.9 Hz, 6H).

Example 172N-Cyclopentyl-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.35 m/z found, 248.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.71 (d, J=7.2 Hz, 1H), 6.10 (d, J=7.2 Hz, 1H),4.62-4.28 (m, 5H), 2.77 (s, 3H), 2.06-2.02 (m, 2H), 1.78-1.57 (m, 6H).

Example 173 4-(4-Methylpiperazin-1-yl)-N-(2-phenylethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₆, 297.41 m/z found, 298.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.56 (d, J=7.5 Hz, 1H), 7.26-7.20 (m, 5H), 6.22 (d,J=7.2 Hz, 1H), 5.00-4.50 (m, 4H), 3.80-3.60 (m, 2H), 3.40-3.15 (m, 4H),2.90-2.70 (m, 5H).

Example 174N-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (d, J=7.2 Hz, 1H), 7.38-7.32 (m, 5H), 6.28(d, J=7.2 Hz, 1H), 4.65 (s, 2H), 4.10-3.70 (m, 5H), 2.79 (s, 3H),2.58-2.46 (m, 2H).

Example 1754-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 7.76 (d, J=7.2 Hz, 1H), 7.50-7.30 (m, 5H), 6.24(t, J=7.8Hz, 1H), 5.16 (br s, H), 4.20-3.60 (m, 5H), 2.50 (m, 1H), 2.25(m, 1H), 1.59 (d, J=6.9 Hz, 3H).

Example 176N-(4-Methoxybenzyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅O, 313.41 m/z found, 314.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=6.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 2H),6.94 (d, J=7.5 Hz, 2H), 6.29 (d, J=6.9 Hz, 1H), 4.61 (s, 2H), 4.10-3.80(m, 5H), 3.81 (s, 3H), 2.59 (s, 3H), 2.70-2.50 (m, 1H), 2.40-2.20 (m,1H).

Example 1772-Methyl-1-[(4-piperazin-1-ylpyrimidin-2-yl)amino]propan-2-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.2 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H),4.16 (br s, 2H), 3.91 (br s, 2H), 3.37-3.25 (m, 6H), 1.16 (s, 6H).

Example 178N-(4-Fluorobenzyl)-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₈FN₅, 287.34 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 7.43-7.38 (m, 2H),7.13-7.07 (m, 2H), 6.13 (d, J=7.2 Hz, 1H), 4.70-4.50 (m, 2H), 4.60 (s,2H), 4.40-4.28 (m, 3H), 2.79 (s, 3H).

Example 179 44(3R)-3-Aminopyrrolidin-1-yl]N-benzylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.74 (d, J=7.2 Hz, 1H), 7.43-7.27 (m, 5H),6.27-6.22 (m, 1H), 4.62 (s, 2H), 4.09-3.52 (m, 5H), 2.56-2.41 (m, 1H),2.25-2.15 (m, 1H).

Example 18044(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 8.60 (br s, 1H), 7.86 (d, J=7.2 Hz, 1H),7.44-7.25 (m, 5H), 6.16 (d, J=7.5 Hz, 1H), 5.15-5.11 (m, 1H), 3.91-3.54(m, 5H), 2.57 (s, 3H), 2.38-2.27 (m, 2H), 1.53 (d, J=6.9 Hz, 3H).

Example 1814-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1H), 6.27 (dd, J=7.2, 6.9 Hz,1H), 4.20-3.60 (m, 6H), 2.61-2.48 (m, 1H), 2.31-2.22 (m, 1H), 2.05-1.69(m, 5H), 1.50-1.20 (m, 5H).

Example 182N-(2-Methoxyethyl)-443-(methylamino)azetidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.79 (d, J=7.2 Hz, 1H), 6.16 (d, J=7.2 Hz, 1H),4.72-4.61 (m, 2H), 4.47-4.33 (m, 3H), 3.63 (br s, 4H), 3.43 (s, 3H),2.80 (s, 3H).

Example 1834-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.1 [M+H]⁺.Amine ¹H NMR (300 MHz, CDCl₃): 7.82 (d, J=6.0 Hz, 1H), 7.33-7.23 (m,5H), 5.68 (d, J=6.0 Hz, 1H), 4.91 (br s, 1H), 3.66-3.30 (m, 7H), 2.90(t, J=7.2 Hz, 2H), 2.48 (s, 3H), 2.48-2.14 (m, 1H), 1.90-1.80 (m, 1H)Salt ¹H NMR (300 MHz, CD₃OD): 7.75 (d, J=6.6 Hz, 1H), 7.40-7.20 (m, 5H),6.28 (d, J=6.6 Hz, 1H), 4.20-3.60 (m, 7H), 3.10-2.90 (m, 2H), 2.85 (s,3H), 2.70-2.20 (m, 2H)

Example 1844-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=6.6 Hz, 1H), 6.28 (d, J=6.6 Hz, 1H),4.05-3.56 (m, 6H), 2.84 (s, 3H), 2.73-2.20 (m, 3H), 2.05-1.78 (m, 5H),1.32 (s, 3H), 1.27-1.05 (m, 7H).

Example 1854-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methoxybenzyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅O, 299.38 m/z found, 300.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H),6.91 (d, J=7.8 Hz, 2H), 6.27 (t, J=7.2 Hz, 1H), 4.57 (s, 2H), 4.20-3.70(m, 5H), 3.79 (s, 3H), 2.60-2.20 (m, 2H).

Example 1864-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methylbenzyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (d, J=7.5 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H),7.19 (d, J=7.5 Hz, 2H), 6.40-6.20 (m, 1H), 4.62 (s, 2H), 4.20-3.70 (m,5H), 2.50-2.40 (m, 1H), 2.35 (s, 3H), 3.25-2.20 (m, 1H).

Example 187 N-(Cyclopentylmethyl)-4-piperazin-1-ylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.49 (d, J=7.2 Hz, 1H),4.20 (br, s, 2H), 3.95 (br, s, 2H), 3.35-3.26 (m, 6H), 2.19-2.14 (m,1H), 1.77 (br, 2H), 1.64-1.56 (m, 4H), 1.28-1.22 (m, 2H).

Example 188443-(Methylamino)azetidin-1-yl]-N-(pyridin-2-ylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.34 m/z found, 271.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.64 (d, J=4.8 Hz, 1H), 8.19-8.14 (m, 1H),7.81-7.61 (m, 3H), 6.13 (d, J=7.2 Hz, 1H), 4.57-4.55 (m, 1H), 4.38 (br,s, 2H), 4.21 (br, s, 2H), 2.73 (s, 3H).

Example 1894-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(3S,5S,7S)-tricyclo[3.3.1.1.3.7]dec-1-ylmethyl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₁N₅, 341.5 m/z found, 342.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.93 (d, J=7.2 Hz, 1H), 6.43 (d, J=6.9 Hz, 1H),4.28-3.91 (m, 5H), 3.38 (s, 2H), 2.99 (s, 3H), 2.78-2.70 (m, 1H),2.56-2.45 (m, 1H), 2.18 (s, 3H), 1.99-1.85 (m, 6H), 1.78 (s, 6H).

Example 1904-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.94 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz, 1H),4.70-4.60 (m, 1H), 4.30-3.90 (m, 5H), 2.98 (s, 3H), 2.80-2.40 (m, 3H),2.20-1.40 (m, 6H), 1.21 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H).

Example 191N-(Cyclohexylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₇N₅, 289.43 m/z found, 290.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (d, J=7.2 Hz, 1H), 6.30-6.20 (m, 1H),4.10-3.75 (m, 5H), 3.40-3.30 (m, 2H), 2.83 (s, 3H), 2.62-2.56 (m, 1H),2.45-2.38 (m, 1H), 1.90-1.60 (m, 6H), 1.40-0.99 (m, 5H).

Example 192N-Cyclohexyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.76 (d, J=7.2 Hz, 1H), 6.24 (d, J=6.9 Hz, 1H),4.10-3.70 (m, 6H), 2.81 (s, 3H), 2.60-2.30 (m, 2H), 2.06-1.70 (m, 5H),1.49-1.33 (m, 5H).

Example 193N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.68 (d, J=7.5 Hz, 1H), 6.20 (d J=7.2 Hz, 1H),4.10-3.40 (m, 6H), 2.89 (d, J=7.8 Hz, 1H), 2.75 (s, 3H), 2.60-2.20 (m,3H), 2.03-1.90 (m, 6H), 1.57-1.50 (m, 1H), 1.20 (s, 3H), 1.06 (s, 3H),0.91 (d, J =9.9 Hz, 1H).

Example 1944-(1,4-Diazepan-1-yl)-N-(2,2-dimethylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.39 m/z found, 264.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.84 (d, J=7.5 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H),4.29-4.08 (m, 3H), 3.89-3.85 (m, 1H), 3.60-3.20 (m, 6H), 2.33-2.24 (m,2H), 1.04 (s, 9H).

Example 195N-Bicyclo[2.2.1]hept-2-yl-4-(1,4-diazepan-1-yl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.82 (d, J=7.5 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H),4.30-3.70 (m, 5H), 3.60-3.40 (m, 4H), 2.40-2.20 (m, 4H), 1.93-1.87 (m,1H), 1.71-1.23 (m, 7H)

Example 196 4-[(35)-3-Aminopyrrolidin-1-yl]-N-butylpyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.33 m/z found, 236.2 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.64 (d, J=7.2 Hz, 1H), 6.19 (s, 1H), 3.72-4.21 (m,5H), 3.38-3.44 (s, 2H), 2.49-2.60 (m, 1H), 2.25-2.34 (m, 1H), 1.58-1.66(m, 2H), 1.37-1.44 (m, 2H), 0.92-0.97 (t, J=7.2 Hz, 3H).

Example 1974-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclohexylmethyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.75 (d, J=7.5 Hz, 1H), 6.27 (d, J=7.5 Hz, 1H),4.14-3.68 (m, 5H), 2.61-2.49 (m, 1H), 2.31-2.21 (m, 1H), 1.79-1.69 (m,6H), 1.28-1.16 (m, 4H), 1.04-0.97 (m, 2H).

Example 1984-[(35)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.33 m/z found, 236.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.51 (d, J=7.2 Hz, 1H), 6.07 (s, 1H), 4.07-4.09 (m,1H), 3.60-3.95 (m, 4H), 3.15 (s, 2H), 2.34-2.49 (m, 1H), 2.10-2.23 (m,1H), 0.83 (d, J=6.6 Hz, 6H).

Example 1994-[(3S)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyppyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₈FN₅, 287.34 m/z found, 288.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.49 (d, J=7.5 Hz, 1H), 7.24-7.29 (m, 2H), 6.95 (m,2H), 5.98 (m, 1H), 4.45 (s, 2H), 3.95-4.04 (m, 1H), 3.56-3.82 (m, 4H),2.20-2.41 (m, 1H), 1.98-2.18 (m, 1H).

Example 2004-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.37 m/z found, 285.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.81 (s, 1H), 8.58 (s, 1H), 8.13 (d, J=6.3 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=4.8 Hz, 1 H), 6.35 (d, J=6.3 Hz, 1H), 5.06(s, 2H), 4.00-3.54 (m, 5H), 2.76 (s, 3H), 2.54-2.24 (m, 2H).

Example 201N-Cyclopentyl-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.51 (d, J=7.2 Hz, 1H), 6.07 (s, 1H), 3.83-4.09 (m,3H), 3.64-3.76 (m, 3H), 2.70 (s, 3H), 2.40-2.50 (m, 1H), 2.17-2.27 (m,1H), 1.90-1.93 (m, 2H), 1.50-1.60 (m, 6H).

Example 2024-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.53 (d, J=7.2 Hz, 1H), 6.05 (br s, 1H), 3.91-3.63(m, 5H), 2.70 (s, 3H), 2.50-2.38 (m, 1H), 2.26-2.15 (m, 1H), 1.87-1.78(m, 1H), 0.84 (d, J=6.6 Hz, 6H).

Example 203N-(2,2-Dimethylpropyl)-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.39 m/z found, 264.1 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 7.54 (d, J=7.2 Hz, 1H), 6.05 (s, 1H), 3.75-3.91 (m,3H), 3.62-3.71 (m, 3H), 3.18-3.26 (m, 2H), 2.70 (s, 3H), 2.38-2.50 (m,1H), 2.15-2.28 (m, 1H), 0.85 (s, 9H).

Example 204N-Benzyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, MISSING ¹H NMR(300 MHz, CD₃OD): 7.79 (d, J=7.2 Hz, 1H), 7.41-7.31 (m, 5H), 6.30 (d, J=6.9 Hz, 1H), 4.68 (s, 2H), 4.06-3.77 (m, 5H), 2.82 (s, 3H), 2.62-2.21(m, 2H).

Example 2054-[(3R)-3-Aminopyrrolidin-1-yl]-N-R1r,5R,7S)-tricyclo[3.3.1.1.3.7]dec-2-yl]pyrimidin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₇N₅, 313.45 m/z found, 314.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.81 (d, J=7.5 Hz, 1H), 6.28 (t, J=7.2 Hz, 1 H),4.20-3.61 (m, 6H), 2.60-2.49 (m, 1H), 2.31-2.21 (m, 1H), 2.10-1.72 (m,14H).

The compounds in Example 206 through Example 253 were prepared usingmethods analogous to those described in Example 21 Method B.

Example 2064-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.62 (d, J=7.5 Hz, 1H), 6.42 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.93 (s, 1H), 4.11-3.69 (m, 6H), 2.88 (s, 3H), 2.67-2.57 (m,2H), 2.43-2.39 (m, 1H), 2.00-1.35 (m, 6H), 1.11 (s, 3H), 1.02 (s, 3H),0.98 (s, 3H).

Example 207Adamantan-2-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.65 (d, J=7.8 Hz, 1H), 6.67 (dd, J=2.1 Hz, 7.8Hz, 1H), 6.32 (s, 1H), 4.30 (d, J=14 Hz, 2H), 3.86 (s, 1H), 3.68 (d,J=12 Hz, 2H), 3.50 (t, J=13 Hz, 2H), 3.40-3.20 (m, 2H), 2.99 (s, 3H),2.20-1.70 (m, 14H).

Example 208Adamantan-2-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.65 (d, J=7.5 Hz, 1H), 6.43 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.96 (d, J=2.1 Hz, 1H), 4.12-3.69 (m, 6H), 2.88 (s, 3H),2.66-2.59 (m, 1H), 2.42-2.35 (m, 1H), 2.20-1.75 (m, 14H).

Example 209N-[(1R)-1-Cyclohexylethyl]-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₃₀N₄, 302.47 m/z found, 303.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.5 Hz, 1H), 6.37 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 4.08-3.53 (m, 6H), 2.84 (s, 3H),2.62-2.55 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.71 (m, 5H), 1.60-1.05 (m,6H), 1.24 (d, J=6.6 Hz, 3H).

Example 210Adamantan-1-yl-[4-(35)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.53 (d, J=7.5 Hz, 1H), 6.31 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.80 (s, 1H), 4.00-3.50 (m, 5H), 2.73(s, 3H), 2.50-2.46 (m,1H), 2.30-2.20 (m, 1H), 2.13 (s, 3H), 2.01 (s, 6H), 1.75 (s, 6H).

Example 211N-(Cyclohexylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₈N₄, 288.44 m/z found, 289.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.2 Hz, 1H), 6.37 (dd, J=2.4 Hz, 7.2Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 4.04-3.60 (m, 5H), 3.12 (d, J=7.2 Hz,2H), 2.82 (s, 3H), 2.58-2.53 (m, 1H), 2.40-2.20 (m, 1H), 1.87-1.64 (m,6H), 1.40-1.02 (m, 5H).

Example 212N-(Cyclohexylmethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₈N₄, 288.44 m/z found, 289.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.63 (d, J=7.2 Hz, 1H), 6.68 (d, J=7.8Hz, 1H),6.17(s, 1H), 4.32 (d, J=14.1 Hz, 2H), 3.69 (d, J=12.8 Hz, 2H), 3.50 (t,J =13.6 Hz, 2H), 3.34-3.23 (m, 2H),3.18 (d, J=7.2 Hz, 2H), 3.01 (s, 3H),1.90-1.66 (m, 6H), 1.37-1.30 (m, 3H), 1.13-1.05 (m, 2H).

Example 213N-[(1R)-1-Cyclohexylethyl]-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₃₀N₄, 302.47 rrilz found, 303.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.58 (d, J=7.2 Hz, 1H), 6.39 (d, J=7.5 Hz, 1H),5.83 (s, 1H), 4.08-3.55 (m, 6H), 2.86 (s, 3H), 2.70-2.50 (m, 1H),2.40-2.20 (m, 1 H), 1.93-1.73 (m, 5H), 1.60-1.08 (m, 6H), 1.26 (d, J=6.3Hz, 3H).

Example 214N-[(1R)-1-CyclohexylethyI]-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₃₀N₄, 302.47 rrilz found, 303.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.61 (d, J=7.5 Hz, 1H), 6.65 (dd, J=2.4 Hz, 7.5Hz, 1H), 6.18 (d, J=2.4 Hz, 1 H), 4.30 (d, J=14 Hz, 2H), 3.70-3.46 (m,5H), 3.40-3.20 (m, 2H), 3.00 (s, 3H), 1.91-1.71 (m, 5H), 1.60-1.05 (m,6H), 1.25 (d, J=6.6 Hz, 3H).

Example 215Adamantan-2-yl-[4-(35)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.65 (d, J=7.5 Hz, 1H), 6.43 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.96 (d, J=1.8 Hz, 1H), 4.12-3.69 (m, 6H), 2.88 (s, 3H),2.67-2.59 (m, 1H), 2.43-2.36 (m, 1H), 2.20-1.75 (m, 14H).

Example 216 3-{[4-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J =7.5 Hz, 1H), 6.62-6.59 (m, 1H), 4.25(d, J=14.4 Hz, 2H), 3.66-3.59 (m, 4H), 3.48-3.15 (m, 6H), 2.93 (s, 3H),1.86-1.78 (m, 2H).

Example 217N-{[(1S,2S,5S)-6,6-Dirnethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.55 (d, J=7.2 Hz, 1H), 6.36 (dd, J=2.1 Hz, 7.2Hz, 1H), 5.74 (s, 1H), 4.10-3.50 (m, 5H), 3.40-3.20 (m, 2H), 2.81 (s,3H), 2.56-2.33 (m, 4H), 2.31-1.94 (m, 5H), 1.60-1.50 (m, 1H), 1.24 (s,3H), 1.09 (s, 3H), 0.97 (d, J=9.9 Hz, 1H)

Example 218Adamantan-1-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.2 [M+H]⁺. ¹ HNMR (300 MHz, CD₃OD): 7.54 (d, J=7.5 Hz, 1H), 6.32 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.81 (d, J=2.1 Hz, 1H), 4.00-3.50 (m, 5H), 2.76 (s, 3H),2.53-2.48 (m, 1H), 2.33-2.28 (m, 1H), 2.12 (br s, 3H), 2.01 (s, 6H),1.75 (s, 6H).

Example 219Adamantan-1-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₀H₃₀N₄, 326.49 m/z found, 327.2 [M+H]⁺. ¹ HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.8 Hz, 1H), 6.61 (dd, J=2.4 Hz, 7.5Hz, 1H), 6.15 (d, J=2.1 Hz, 1H), 4.30-4.10 (m, 2H), 3.70-3.40 (m, 6H),2.93 (s, 3H), 2.13 (s, 3H), 2.01 (s, 6H), 1.75 (t, J=14 Hz, 6H).

Example 220Adamantan-1-ylmethyl44-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₁ H ₃₂ N₄, 340.52 m/z found, 341.3 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD): 7.61 (d, J=7.5 Hz, 1 H), 6.41 (dd, J =2.1 Hz,7.5 Hz, 1H), 5.91 (d, J=2.1 Hz, 1H), 4.12-3.69 (m, 5H), 3.05 (s, 2H),2.88 (s, 3H), 2.66-2.59 (m, 1H), 2.43-2.40 (m, 1H), 2.36 (s, 3H), 1.82(dd, J=12 Hz, 27 Hz, 6H), 1.70 (s, 6H).

Example 221N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.2 Hz, 1H), 6.64 (dd, J=2.1 Hz, 7.5Hz, 1 H), 5.74 (d, J=2.1 Hz, 1H), 4.27 (d, J=14 Hz, 2H), 3.64 (d, J=12Hz, 2H), 3.45 (dd, J=14 Hz, 12 Hz, 2H), 3.40-3.20 (m, 4H), 2.97 (s, 3H),2.43-2.38 (m, 2H), 2.04-1.94 (m, 5H), 1.60-1.50 (m, 1H), 1.24 (s, 3H),1.09 (s, 3H), 0.98 (d, J=9.6 Hz, 1H).

Example 2224-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄O, 276.38 m/z found, 277.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.62 (d, J=7.5 Hz, 1H), 6.43 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.85 (d, J=2.1 Hz, 1H), 4.06-3.61 (m, 10H), 2.86 (s, 3H),2.70-2.50 (m, 1H), 2.45-2.35 (m, 1H), 2.10-2.00 (m, 2H), 1.70-1.69 (m,2H).

Example 2234-(4-Methylpiperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄O, 276.38 m/z found, 277.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.67 (d, J=7.5 Hz, 1H), 6.64 (dd, J=2.4 Hz, 7.5Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 4.35 (d, J=14 Hz, 2H), 4.05-4.01 (m,2H), 3.88-3.48 (m, 7H), 3.40-3.20 (m, 2H), 3.04 (s, 3H), 2.10-1.90 (m,2H), 1.72-1.64 (m, 2H).

Example 224N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.55 (d, J=7.5 Hz, 1H), 6.36 (dd, J=2.1 Hz, 7.2Hz, 1H), 5.74 (d, J=1.8 Hz, 1H), 4.10-3.60 (m, 5H), 3.40-3.20 (m, 2H),2.81 (s, 3H), 2.60-2.20 (m, 4H), 2.10-1.90 (m, 5H), 1.70-1.50 (m, 1H),1.24 (s, 3H), 1.09 (s, 3H), 0.97 (d, J=9.6 Hz, 1 H).

Example 225N-(Cyclohexylmethyl)-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₈N₄, 288.44 m/z found, 289.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.2 Hz, 1H), 6.37 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.77 (d, J=2.4 Hz, 1H), 4.10-3.50 (m, 5H), 3.12 (d, J=6.9 Hz,2H), 2.82 (s, 3H), 2.60-2.53 (m, 1H), 2.36-2.29 (m, 1H), 1.87-1.60 (m,6H), 1.38-1.02 (m, 5H).

Example 226N-(Cyclopentylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₆N₄, 274.41 m/z found, 275.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.2 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),5.78 (s, 1H), 4.04-3.62 (m, 5H), 3.20 (d, J=7.2 Hz, 2H), 2.82 (s, 3H),2.60-2.51 (m, 1H), 2.40-2.17 (m, 2H), 1.89-1.62 (m, 6H), 1.34-1.28 (m,2H).

Example 227N-(Cyclopentylmethyl)-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₆N₄, 274.41 m/z found, 275.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.5 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),5.78 (s, 1H), 4.04-3.62 (m, 5H), 3.20 (d, J=7.2 Hz, 2H), 2.82 (s, 3H),2.58-2.53 (m, 1H), 2.36-2.19 (m, 2H), 1.89-1.62 (m, 6H), 1.34-1.30 (m,2H).

Example 228N-Cyclopentyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.5 Hz, 1H), 6.37 (d, J=7.5 Hz, 1H),5.76 (s, 1H), 4.05-3.62 (m, 6H), 2.82 (s, 3H), 2.60-2.53 (m, 1H),2.39-2.33 (m, 1H), 2.11-2.06 (m, 2H), 1.83-1.56 (m, 6H).

Example 2294-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.73 (br s, 1H), 9.60 (br s, 2H), 8.72 (d,J=4.5 Hz, 1H), 8.29-8.10 (m, 2H), 7.73-7.36(m, 3H), 6.34 (d, J=5.7 Hz,1H), 5.84 (s, 1H), 4.84 (d, J=5.1 Hz, 2H), 3.90-3.42 (m, 5H), 2.60 (s,3H), 2.40-2.30 (m, 2H).

Example 2304-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-R1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.39 (br s, 1H), 9.61 (br s, 2H), 8.05 (d,J=8.4 Hz, 1 H), 7.66 (m, 1H), 6.29 (d, J=6.9 Hz, 1 H), 5.75 (s, 1H),3.96-3.40 (m, 6H), 2.60 (s, 3H), 2.50-2.30 (m, 3H), 12.07-1.51 (m, 5H),1.23 (s, 3H), 1.05 (m, 7H).

Example 231N-Bicyclo[2.2.1]hept-2-yl-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₆N₄, 286.42 m/z found, 287.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.19 (br s, 1H), 9.59 (br s, 2H), 7.90 (d,J=6.0 Hz, 1 H), 7.67 (br s, 1H), 6.28 (d, J=6.9 Hz, 1 H), 5.65 (s, 1H),3.89-3.50 (m, 6H), 2.59 (s, 3H), 2.33-2.17 (m, 4H), 1.85-1.79 (m, 1H),1.48-1.09 (m, 7H).

Example 2324-(4-Methylpiperazin-1-yl)-N-R1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.53 (d, J=7.5 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H),6.11 (s, 1H), 4.20 (d, J=14 Hz, 2H), 3.89-3.84 (m, 1 H), 3.57 (d, J=12Hz, 2H), 3.42 (t, J=13 Hz, 2H) 3.17 (t, J=13 Hz, 2H), 2.89 (s, 3H),2.72-2.64 (m, 1H), 2.40-2.35 (m, 1H), 2.05-1.55 (m, 4H), 1.18 (s, 3H),1.07 (d, J=7.2 Hz, 3H), 1.05-1.00 (m, 1H), 1.00 (s, 3H).

Example 233N-tert-Butyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₄N₄, 248.37 m/z found, 249.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.55 (d, J=7.5 Hz, 1H), 6.34-6.31 (m, 1H), 5.77(s, 1H), 4.01-3.59 (m, 5H), 2.77 (s, 3H), 2.532.49 (m, 1H), 2.33-2.29(m, 1H), 1.43 (s, 9H).

Example 2343-({4-[(35)-3-(Methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.47 (d, J=7.5 Hz, 1H), 6.27 (d, J=7.2 Hz, 1H),5.70 (br, 1H), 3.94-3.21 (m, 10H), 2.72 (s, 3H), 2.48-2.43 (m, 1H),2.27-2.23 (m, 1H), 1.81-1.73 (m, 2H).

Example 235N-Cyclopropyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₀N₄, 232.33 m/z found, 233.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.52 (d, J=7.5 Hz, 1H), 6.33 (dd, J=7.5 Hz, J =2.1Hz, 1H), 5.76 (d, J=1.5 Hz, 1H), 3.96-3.52 (m, 4H), 2.52-2.41 (m, 2H),2.30-2.21 (m, 1H), 0.88-0.82 (m, 2H), 0.56-0.51 (m, 2H).

Example 236N-(Cyclopentylmethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₆N₄, 274.41 m/z found, 275.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.61 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H),6.16 (s, 1H), 4.29 (d, J=14 Hz, 2H), 3.66 (d, J=12 Hz, 2H), 3.48 (t,J=13 Hz, 2H), 3.40-3.20 (m, 2H), 3.22 (d, J=7.2 Hz, 2H), 2.98 (s, 3H),2.27-2.17 (m, 1H), 1.90-1.62 (m, 6H), 1.34-1.30 (m, 2H).

Example 237N-Benzyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₂N₄, 282.39 m/z found, 283.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.49 (br s, 1H), 9.53 (br s, 2H), 8.22 (s, 1H),7.69 (s, 1H), 7.41-7.33 (m, 5H), 6.30 (d, J=6.9 Hz, 1H), 5.75 (s, 1H),4.55 (d, J=5.4 Hz, 2H), 3.89-3.50 (m, 5H), 2.60 (s, 3H), 2.40-2.20 (m,2H).

Example 238N-(2-Methoxyethyl)-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.5 Hz, 1H), 6.38 (dd, J=7.5 Hz, J =2.4Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 4.05-4.02 (m, 1H), 3.93-3.89 (m, 2H),3.71-3.32 (m, 6H), 3.31 (s, 3H), 2.82 (s, 3H), 2.61-2.54 (m, 1H),2.37-2.30 (m, 1 H).

Example 239 N-(2-Methoxyethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.64 (d, J=7.5 Hz, 1H), 6.67 (dd, J=7.8 Hz, J =2.4Hz, 1H), 6.20 (d, J=2.1 Hz, 1 H), 4.3 (d, J=14.4 Hz, 2H), 3.67-3.21 (m,13H), 2.98 (s, 3H).

Example 2402-Methyl-1-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol

MS (ESI): mass calcd. for C₁₄H₂₄N₄O, 264.37 m/z found, 265.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.2 Hz, 1H), 6.37 (br d, J=6.0 Hz, 1H), 5.88 (s, 1H), 4.03-3.63 (m, 5H), 3.26 (s, 2H), 2.82 (s, 3H),2.58-2.53 (m, 1 H), 2.36-2.32 (m, 1H), 1.29 (s, 6H).

Example 2412-Methyl-1-{[4-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}propan-2-ol

MS (ESI): mass calcd. for C₁₄H₂₄N₄O, 264.37 m/z found, 265.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.69 (d, J=7.8 Hz, 1H), 6.71 (br d, J=5.7 Hz, 1H),6.30 (s, 1H), 4.36 (d, J=14 Hz, 2H), 3.72-3.48 (m, 6H), 3.30-3.20 (m,2H), 3.03 (s, 3H), 1.34 (s, 6H).

Example 2422-Methyl-1-({4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol

MS (ESI): mass calcd. for C₁₄H₂₄N₄O, 264.37 m/z found, 265.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.5 Hz, 1H), 6.36 (d, J=7.5 Hz, 1H),5.87 (s, 1H), 4.06-3.63 (m, 5H), 3.27 (s, 2H), 2.83 (s, 3H), 2.61-2.51(m, 1H), 2.40-2.31 (m, 1H), 1.30 (s, 6H).

Example 243N-Butyl-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₄N₄, 248.37 m/z found, 249.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.2 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H),5.79 (s, 1H), 4.07-3.64 (m, 5H), 3.31 (t, J=7.2 Hz, 2H), 2.84 (s, 3H),2.63-2.56 (m, 1H), 2.42-2.36 (m, 1H), 1.73-1.63 (m, 2H), 1.55-1.48 (m,2H), 1.01 (t, J=7.5 Hz, 3H).

Example 2444-(4-Methylpiperazin-1-yl)-N-(pyridin-2-ylmethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.89 (d, J=4.5 Hz, 1H), 8.62 (m, 1H), 8.13-8.05(m, 2H), 7.80 (d, J=7.2 Hz, 1H), 6.82 (d, J=6.6 Hz, 1H), 6.37 (s, 1 H),5.16 (s, 2H), 4.43 (d, J=13 Hz, 2H), 3.69-3.53 (m, 4H), 3.30-3.20 (m,2H), 3.01 (s, 3H).

Example 2454-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₄N₄, 296.42 m/z found, 297.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.40 (br s, 1H), 9.64 (br s, 2H), 7.81 (s, 1H),7.67 (s, 1H), 7.33-7.25 (m, 5H), 6.29 (s, 1 H), 5.69 (s, 1H), 3.89-3.50(m, 7H), 2.97-2.88 (m, 2H), 2.60 (s, 3H), 2.40-2.20 (m, 2H).

Example 246N-(4-Fluorobenzyl)-4-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₁FN₄, 300.38 m/z found, 301.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.57 (br s, 1H), 9.56 (br s, 2H), 8.25 (s, 1H),7.69 (d, J=6.9 Hz, 1H), 7.48-7.43 (m, 2H), 7.25-7.19 (m, 2H), 6.30 (d,J=6.6 Hz, 1 H), 5.73 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.89-3.61 (m, 5H),2.59 (s, 3H), 2.40-2.20 (m, 2H).

Example 2474-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-R1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.62 (d, J=7.2 Hz, 1H), 6.42 (dd, J=2.1 Hz, 7.2Hz, 1H), 5.92 (d, J=2.1 Hz, 1H), 4.11-3.69 (m, 6H), 2.87 (s, 3H),2.64-2.56 (m, 2H), 2.42-2.37 (m, 1H), 2.00-1.35 (m, 6H), 1.11 (s, 3H),1.02 (s, 3H), 0.98 (s, 3H).

Example 248 N-Cyclopentyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, MISSING ¹H NMR(300 MHz, CD₃OD): 7.60 (d, J=7.8 Hz, 1H), 6.64 (d, J=7.5 Hz, 1H), 6.11(s, 1 H), 4.27 (d, J=14 Hz, 2H), 3.99-3.97 (m, 1 H), 3.64 (d, J=12 Hz,2H), 3.45 (t, J=14 Hz, 2H), 3.22 (t, J=11 Hz, 2H), 2.97 (s, 3H),2.09-2.05 (m, 2H), 2.18-1.57 (m, 6H).

Example 249 N-(4-FluorobenzyI)-4-(4-methylpiperazin-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₁FN₄, 300.38 m/z found, 301.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.66 (d, J=7.5 Hz, 1H), 7.47-7.42 (m, 2H),7.17-7.12 (m, 2H), 6.70 (d, J=7.2 Hz, 1H), 6.16 (s, 1H), 4.55 (s, 2H),4.30 (d, J =14 Hz, 2H), 3.67 (d, J=12 Hz, 2H), 3.47 (t, J=13 Hz, 2H),3.24 (t,J=12 Hz, 2H), 2.99 (s, 3H).

Example 250: 4-(4-Methylpiperazin-1-yl)-N-(2-phenylethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₄N₄, 296.42 m/z found, 297.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.66 (s, 1H), 11.64 (br s, 1H), 7.93 (s, 1H),7.70 (s, 1H), 7.30-7.22 (m, 5H), 6.59 (d, J=6.9 Hz, 1H), 6.08 (s, 1 H),4.69 (br s, 2H), 4.19 (d, J=13 Hz, 2H), 3.51-3.46 (m, 4H), 3.08-2.84 (m,4H), 2.76 (s, 3H).

Example 251Adamantan-1-ylmethyl44-(35)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₁ H ₃₂ N₄, 340.52 m/z found, 341.2 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD): 7.61 (d, J=7.5 Hz, 1 H), 6.41 (dd, J =1.8 Hz,7.5 Hz, 1H), 5.91 (d, J=1.5 Hz, 1H), 4.11-3.69 (m, 5H), 3.05 (s, 2H),2.88 (s, 3H), 2.66-2.59 (m, 1H), 2.43-2.40 (m, 1H), 2.38 (s, 3H), 1.82(dd, J=12 Hz, 27 Hz, 6H), 1.70 (s, 6H).

Example 2524-(4-Methylpiperazin-1-yl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₀H₃₂N₄, 328.5 m/z found, 329.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.60 (d, J=7.8 Hz, 1H), 6.63 (dd, J=2.4 Hz, 7.8Hz, 1H), 6.23 (d, J=2.1 Hz, 1H), 4.26 (d, J=14 Hz, 2H), 3.90 (dd, J=2.1Hz, 11 Hz, 1H), 3.65 (d, J=12 Hz, 2H), 3.47 (t, J=13 Hz, 2H), 3.40-3.20(m, 2H), 2.97 (s, 3H), 2.54-2.46 (m, 1H), 1.86-1.73 (m, 3H), 1.53-1.27(m, 2H), 1.10-0.90 (m, 1H), 1.04 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H).

Example 253N-(Bicyclo[2.2.1]hept-2-ylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₈N₄, 300.45 m/z found, [M+H]⁺. ¹H NMR(300 MHz, CD₃OD): 7.61 (d, J=7.2 Hz, 1H), 6.41 (dd, J=7.2 Hz, 2.1 Hz,1H), 5.83 (d, J=2.1 Hz, 1H), 4.09-4.06 (m, 1H), 3.97-3.91 (m, 1H),3.75-3.66 (m, 3H), 3.36-3.18 (m, 2H), 2.86 (s, 3H), 2.64-2.57 (m, 1H),2.40-2.21 (m, 3H), 1.92-1.90 (m, 1H), 1.63-1.23 (m, 7H), 0.85-0.79 (m,1H).

Example 254 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyridin-2-amine

4-bromo-N-butylpyridin-2-amine. A solution of 4-bromo-2-fluoropyridine(2.0 g, 11.3 mmol) and n-butan-1-amine (752 mg, 10.3 mmol) inN-methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at 100° C. for 1 hr.The reaction was allowed to cool to room temperature and diluted withDCM (50 mL), washed with water (10 mL * 2). The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (0-20% EtOAc-petrolumn ether gradient elution) toafford the desired product (1.4 g, 45%). ¹H NMR (300 MHz, CDCl₃): 7.88(d, J=5.4 Hz, 1H), 6.70 (d, J=5.4 Hz, 1H), 6.54 (s, 1H), 4.60 (br s,1H), 3.26-3.19 (m, 2H), 1.63-1.56 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t,J=7.2 Hz, 3H).

(R)-tert-butyl 1-(2-(butylamino)pyridin-4-yl)pyrrolidin-3-ylcarbamate.To a solution of 4-bromo-N-butylpyridin-2-amine (458 mg, 2 mmol),(R)-tert-butyl pyrrolidin-3-ylcarbamate (410 mg, 2.2 mmol) in anhydrousdioxane (12 mL) was added Pd₂(dba)₃ (200 mg, 0.22 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xant-phos) (200 mg,0.24 mmol) and t-BuONa (576 mg, 6 mmol) under atmosphere of argen. Theresulting reaction was stirred at 100° C. for 2 hrs and diluted withwater (40 mL), extracted with DCM, The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography (0-10% MeOH-DCM gradient elution)to afford the crude product (purity>70%).

(R)-4-(3-aminopyrrolidin-1-yl)-N-butylpyridin-2-amine dihydrochloride.Crude product obtained above was dissolved in MeOH (6mL) and ethersolution of HCl gas (ca. 4N, 10 mL) was added. The resulting reactionwas stirred at ambient temperature for 20 hrs. The reation wasconcentrated under reduced pressure and purified by prep-HPLC to affordthe desired product (50mg, 6.7% yield in two steps). ¹H NMR (300 MHz,CD₃OD): 7.59 (d, J=7.5 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H), 5.79 (s, 1H),4.89 (m, 1H), 4.15 (m, 1H), 3.74-3.66 (m, 3H), 3.38-3.29 (m, 2H),2.60-2.53 (m, 1H), 2.34-2.30 (m, 1H), 1.73-1.64 (m, 2H), 1.56-1.46 (m,2H), 1.02 (t, J=7.5 Hz, 3H); LC-MS: m/z=235.2 [M+H]⁺, t_(R)=0.92 min;HPLC: 100% (214nm), 97% (254nm), t_(R)=4.84 min.

The compounds in Example 255 through Example 297 were prepared usingmethods analogous to those described in Example 254.

Example 255Adamantan-1-ylmethyl44-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₁ H₃₂N₄, 340.52 m/z found, 341.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.66 (d, J=7.2 Hz, 1 H), 6.69 (dd, J =2.4 Hz, 7.5Hz, 1H), 5.29 (d, J=2.1 Hz, 1H), 4.40-4.20 (m, 2H), 3.80-3.20 (m, 6H),3.07 (s, 2H), 3.04 (s, 3H), 2.07 (s, 3H), 1.82 (dd, J=12 Hz, 27 Hz, 6H),1.70 (s, 6H).

Example 256N-(Cyclohexylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₈H₂₈N₄, 300.45 m/z found, 301.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.5 Hz, 1H), 6.37 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.78 (d, J=2.1 Hz, 1H), 4.55-4.45 (m, 1H), 3.95-3.78 (m, 3H),3.51-3.37 (m, 4H), 3.12 (d, J=6.9 Hz, 2H), 2.41-2.33 (m, 1 H), 2.20-2.00(m, 1H), 1.87-1.64 (m, 6H), 1.40-1.02 (m, 5H).

Example 2574-[(3aR,6aR)-Hexahydropyrrolo[3,4-1D]pyrrol-5(1H)-yl]-N-(2-methylpropyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J=7.5 Hz, 1H), 6.39 (d, J=7.2 Hz, 1H),5.81 (s, 1H), 4.51-4.48 (m, 1H), 4.02-3.76 (m, 3H), 3.53-3.39 (m, 4H),3.12 (d, J=6.9 Hz, 2H), 2.39-2.35 (m, 1H), 2.14-1.93 (m, 2H), 1.04 (d,J=6.6 Hz, 6H).

Example 2584-[(35)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₆, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.84 (d, J=5.7 Hz, 1H), 8.60 (t, J=7.8 Hz, 1H),8.11-7.99 (m, 2H), 7.69 (d, J=7.2 Hz, 1 H), 6.46 (d, J=6.6 Hz, 1H), 5.90(s, 1H), 5.09 (s, 2H), 4.09 (br, s, 1H), 3.85-3.34 (m, 4H), 2.58-2.45(m, 1H), 2.28-2.22 (m, 1H).

Example 259 N-Cyclopentyl-4[3-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₂N₄, 246.36 m/z found, 247.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.21 (br, s, 1H), 10.06 (br, s, 2H), 8.10 (br,s, 1H), 7.80-7.60 (m, 1H), 6.08 (d, J=6.6 Hz, 1H), 5.59 (s, 1H), 5.20(br, s, 1 H), 4.32-3.95 (m, 7H), 2.53 (s, 3H), 1.71-1.59 (m, 8H).

Example 260 4-Piperazin-1-yl-N-(pyridin-2-ylmethyl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.85 (d, J=5.7 Hz, 1H), 6.63 (t, J=4.8 Hz, 1H),8.12 (d, J=8.1 Hz, 1H), 8.04 (t, J=6.9 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H),6.77 (d, J=6.9 Hz, 1H), 6.32 (s, 1H), 5.15 (s, 2H), 3.91 (br, s, 4H),3.36-3.30 (m, 4H).

Example 261N-(Cyclopentylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₆N₄, 286.42 m/z found, 287.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J=7.2 Hz, 1H), 6.39 (d, J=7.5 Hz, 1H),5.81 (d, J=1.8 Hz, 1H), 4.52-4.48 (m, 1H), 4.01-3.76 (m, 3H), 3.52-3.37(m, 4H), 3.21 (d, J=7.2 Hz, 2H), 2.42-2.35 (m, 1H), 2.26-2.08 (m, 2H),1.92-1.60 (m, 6H), 1.35-1.29 (m, 2H).

Example 262 N-Cyclopentyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₄N₄, 272.4 m/z found, 273.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.28 (br s, 1H), 9.96 (br s, 1H), 9.68 (br s,1H), 7.97 (d, J=6.9 Hz, 1H), 7.64-7.60 (m, 1H), 6.22 (d, J=6.9 Hz, 1H),5.65 (s, 1H), 4.29-3.65 (m, 7H), 3.40-3.20 (m, 2H), 2.14-1.90 (m, 4H),1.67-1.42 (m, 6H).

Example 2634-[(35)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyppyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₁₉FN₄, 286.36 m/z found, 287.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.54 (s, 1 H), 7.40 (br s, 2H), 7.08-7.04 (m, 2H),6.32 (s, 1H), 5.70 (s, 1H), 4.48 (s, 2H), 3.79 (br s, 1H), 3.90-3.40 (m,4H), 2.47 (br s, 1H), 2.24 (br s, 1H).

Example 2644-[(35)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₀N₄O, 236.32 m/z found, 237.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J=7.5 Hz, 1H), 6.36 (d, J=7.2 Hz, 1H),5.81 (s, 1H), 4.12 (br, s, 1H), 3.89-3.84 (m, 1H), 3.70-3.59 (m, 5H),3.52-3.50 (m, 2H), 3.47-3.34 (m, 5H), 2.56-2.52 (m, 1H), 2.30-2.26 (m, 1H).

Example 265N-Bicyclo[2.2.1]hept-2-yl-4-(1,4-diazepan-1-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₆N₄, 286.42 m/z found, 287.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.64 (d, J=7.5 Hz, 1H), 6.62 (dd, J=7.5 Hz, 2.1Hz, 1H), 5.98 (d, J=2.1 Hz, 1H), 4.04-3.98 (m, 2H), 3.78 (t, J=6.0 Hz,2H), 3.52-3.49 (m, 2H), 3.42-3.36 (m, 3H), 2.41 (br s, 1H), 2.33-2.27(m, 3H), 2.04-1.97 (m, 1H), 1.68-1.60 (m, 3H), 1.50-1.28 (m, 4H).

Example 266Adamantan-2-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₁H₃₀N₄, 338.5 m/z found, 339.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.64 (d, J=7.5 Hz, 1H), 6.43 (dd, J=2.1 Hz, 7.2Hz, 1H), 5.96 (s, 1H), 4.60-4.50 (m, 1 H), 4.04-3.81 (m, 4H), 3.60-3.40(m, 4H), 2.46-2.39 (m, 1H), 2.20-1.75 (m, 15H).

Example 267 4-[(35)-3-Aminopyrrolidin-1-yl]-N-benzylpyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₀N₄, 268.36 m/z found, 269.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J=6.3 Hz, 1H), 7.37-7.28 (m, 5H), 6.34(d, J=6.0 Hz, 1H), 5.72 (s, 1H), 4.52 (s, 2H), 3.80 (br s, 1H),3.90-3.40 (m, 4H), 2.48 (br s, 1H), 2.25 (br s, 1H).

Example 268 4-[(35)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₂N₄, 246.36 m/z found, 247.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.54 (d, J=7.2 Hz, 1H), 6.33 (d, J=6.9 Hz, 1H),5.74 (s, 1H), 4.10-3.61 (m, 6H), 2.55-2.27 (m, 1H), 2.40-2.20 (m, 1H),2.07-2.03 (m, 2H), 1.77-1.56 (m, 6H).

Example 269 4-Pi perazin-1-yl-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₀1\1₄, 314.48 m/z found, 315.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.61 (d, J=7.5 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H),6.17 (d, J=1.8 Hz, 1H), 3.98-3.82 (m, 5H), 3.40-3.30 (m, 5H), 2.80-2.72(m, 1H), 2.50-2.43 (m, 1H), 2.13-2.06 (m, 1H), 2.00-.87 (m, 2H),1.69-1.63 (m, 1H), 1.27 (s, 3H), 1.24-1.08(m, 6H).

Example 2704-[(3R)-3-Aminopyrrolidin-1-yl]-N-bicyclo[2.2.1]hept-2-ylpyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₄N₄, 272.4 m/z found, 273.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.58 (d, J=7.5 Hz, 1H), 6.37 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.71 (d, J=2.1 Hz, 1H), 4.12-3.42 (m, 6H), 2.51-2.48 (m, 1H),2.40-2.21 (m, 3H), 1.95-1.88 (m, 1H), 1.65-1.20 (m, 7H).

Example 271N-[(1R)-1-Cyclohexylethyl]-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₀N₄, 314.48 m/z found, 315.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.55 (d, J=7.5 Hz, 1H), 6.36 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.80 (d, J=2.4 Hz, 1H), 4.55-4.46 (m, 1H), 3.97-3.74 (m, 3H),3.51-3.36 (m, 5H), 2.40-2.33 (m, 1H), 2.20-2.00 (m, 1H), 1.89-1.69 (m,5H), 1.47-1.02 (m, 6H), 1.22 (d, J=6.3 Hz, 3H).

Example 2724-[(35)-3-Aminopyrrolidin-1-yl]-N-R1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₀N₄, 314.48 m/z found, 315.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=6.6 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H),5.79 (s, 1H), 4.10-3.62 (m, 6H), 2.76-2.70 (m, 1H), 2.47 (br s, 2H),2.28 (br s, 1H), 2.08-1.62 (m, 4H), 1.26 (s, 3H), 1.20-1.00 (m, 1H),1.16 (d, J=6.6 Hz, 3H), 1.07 (s, 3H).

Example 2731-({4-[(35)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.26 (s, 1H), 8.54 (br s, 3H), 7.62 (s, 2H),6.22 (s, 1H), 5.79 (s, 1H), 3.93-3.40 (m, 5H), 3.18 (m, 2H), 2.29-2.15(m, 2H), 1.14 (s, 6H).

Example 274 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.60 (d, J=7.2 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H),5.81 (s, 1H), 4.17-3.51 (m, 6H), 2.62-2.53 (m, 1H), 2.40-2.20 (m, 1H),2.07-1.73 (m, 5H), 1.55-1.32 (m, 5H).

Example 275N-(Cyclopentylmethyl)-443-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.39 (br, s, 1H), 10.08 (br, s, 2H), 7.92 (br,s, 1H), 7.69-7.66 (m, 1H), 6.10 (d, J=6.6 Hz, 1H), 5.62 (s, 1H), 4.80(br, s, 1H), 4.34-4.18 (m, 6H), 3.18-3.15 (m, 2H), 2.53 (s, 3H),2.14-2.09 (m, 1H), 1.79-1.24 (m, 8H).

Example 2764-[(35)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₂N₄, 282.39 m/z found, 283.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.35 (s, 1 H), 8.55 (br s, 3H), 7.80 (s, 1H),7.62 (m, 1H), 7.29-7.22 (m, 5H), 6.25 (d, J=6.0 Hz, 1H), 5.66 (s, 1H),4.21-3.48 (m, 7H), 2.85 (m, 2H), 2.29-2.16 (m, 2H).

Example 277 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₄N₄O, 288.4 m/z found, 289.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.60 (d, J=7.5 Hz, 1H), 6.41 (dd, J=2.1 Hz, 7.5Hz, 1H), 5.85 (d, J=1.8 Hz, 1H), 4.57-4.50 (m, 1H), 4.04-3.77 (m, 5H),3.62-2.40 (m, 7H), 2.43-2.33 (m, 1H), 2.20-1.98 (m, 3H), 1.69-1.61 (m,2H).

Example 2784-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.59 (d, J=7.5Hz, 1H), 6.39 (dd, J=7.5 Hz, 1.8 Hz,1H), 5.81 (d, J=1.5 Hz, 1H), 4.89 (m, 1H), 4.15 (m, 1H), 3.89-3.66 (m,3H), 3.23 (d, J=7.5 Hz, 2H), 2.60-2.53 (m, 1H), 2.31-2.22 (m, 2H),1.94-1.90 (m, 2H), 1.75-1.65 (m, 4H), 1.37-1.31 (m, 2H).

Example 2791-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.62 (d, J=7.2 Hz, 1H), 6.39 (d, J=7.2 Hz, 1H),5.90 (s, 1H), 4.19 (m, 1H), 3.89 (m, 1H), 3.73-3.65 (m, 3H), 3.29 (s,2H), 2.58-2.55 (m, 1H), 2.32-2.27 (m, 1H), 1.31 (s, 6H).

Example 280 N-tert-Butyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₃H₂₂N₄, 234.35 m/z found, 235.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.32 (br, s, 1H), 10.13 (br, s, 2H), 7.75-7.71(m, 2H), 6.08 (d, J=5.7 Hz., 1H), 5.51-5.39 (m, 3H), 4.40-4.25 (m, 5H),2.54 (s, 3H), 1.38 (s, 9H).

Example 281 N-Cyclopropyl-4[3-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₁₈N₄, 218.3 m/z found, 219.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.36 (br, s, 1H), 10.21 (br, s, 2H), 8.33 (br,s, 1H), 7.69 (t, J=6.3 Hz, 1H), 6.15 (d, J=5.4 Hz, 1H), 5.63 (s, 1H),4.54 (br,s, 4H), 4.34-4.15 (m, 5H), 2.53 (s, 3H), 0.85-0.84 (m, 2H),0.54 (s, 2H).

Example 2822-Methyl-1-({443-(methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.27 (br, s, 1H), 10.02 (br, s, 2H),7.68-7.61(m, 2H), 6.08 (d. J=6.6 Hz, 1H), 5.69 s, 1H), 4.33-4.20 (m, 7H), 3.17(d, J=5.4 Hz, 2H), 2.54 (s, 3H), 1.16 (s, 6H).

Example 2833-({443-(Methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₀N₄O, 236.32 m/z found, 237.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.47 (br, s, 1H), 10.23 (br, s, 2H), 7.88 (br,s, 1 H), 7.64 (t, J=6.6 Hz, 1H), 6.08 (d, J=6.6 Hz, 1H), 5.59 (s, 1 H),4.71 (br,s, 4H), 4.33-4.15 (m, 5H), 3.49 (t, J=6.3 Hz, 2H), 2.52 (s,3H), 1.73-1.65 (m, 2H).

Example 284443-(Methylamino)azetidin-1-yl]-N-R1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₉H₃₀1\1₄, 314.48 m/z found, 315.3 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.27 (br, s, 1H), 9.97 (br, s, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.6 Hz, 1 H), 6.05 (d, J=6.9 Hz, 1H), 5.61 (s,1H), 4.34-4.15 (m, 7H), 4.15 (br, s, 1H), 2.70-2.63 (m, 1H), 2.55 (s,3H), 2.37 (br, s, 1H), 2.05-1.94 (m, 2H), 1.84-1.81 (m, 1H), 1.53-1.48(m, 1H), 1.09 (s, 3H), 1.06-0.94 (m, 6H).

Example 285 N-Benzyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₀N₄, 268.36 m/z found, 269.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.60 (br, s, 1H), 10.08 (br, s, 2H), 8.32-8.28(m, 1H), 7.70-7.67 (m, 1H), 7.38-7.28 (m, 5H), 6.10 (d, J=7.2 Hz, 1H),5.64 (s, 2H), 5.45 (br, s, 2H), 4.52 (d, J=5.7 Hz, 2H), 4.23-4.14 (m,5H), 2.51 (s, 3H).

Example 286N-(2-Methoxyethyl)-443-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₀N₄O, 236.32 m/z found, 237.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.43 (br, s, 1H), 10.15 (br, s, 2H), 7.78 (br,s, 1H), 7.65 (t, J=6.3 Hz, 1H), 6.10 (d, J=6.6 Hz, 1H), 5.64 (s, 1H),4.36-4.14 (m, 9H), 3.48-3.42 (m, 4H), 3.3 (s, 3H), 2.53 (s, 3H).

Example 287 4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₁ H₃₂N₄, 340.52 m/z found, 341.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.56 (d, J=7.2 Hz, 1H), 6.38 (dd, J=7.5 Hz, J =2.1Hz, 1H), 5.80 (d, J=1.8 Hz, 1H), 4.50-4.46 (m, 1H), 3.98-3.74 (m, 4H),3.50-3.41 (m, 4H), 2.77-2.69 (m, 1H), 2.51-2.30 (m, 2H), 2.14-1.67(m,4H), 1.64-1.63 (m, 1H), 1.28 (s, 3H), 1.18-1.05 (m, 7H).

Example 288 N-tert-Butyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.60 (d, J=7.5 Hz, 1H), 6.37 (d, J=7.2 Hz, 1H),5.82 (s, 1H), 4.49 (t, J=6.6 Hz, 1H), 4.01-3.75 (m, 4H), 3.51-3.30 (m,2H), 2.39-2.32 (m, 1H), 2.12-2.07 (m, 1H), 1.47 (s, 9H).

Example 2894-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₂H₂₀N₄O, 236.32 m/z found, 237.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.52 (d, J=7.2 Hz, 1H), 6.30 (d, J=6.6 Hz, 1H),5.74 (s, 1H), 4.06 (m, 1H), 3.79 (m, 1H), 3.57-3.54 (m, 5H), 3.43-3.39(m, 2H), 3.34 (s, 3H), 2.49-2.44 (m, 1H), 2.21-2.19 (m, 1H).

Example 290 2-Methyl-1-[(4-piperazin-1-ylpyridin-2-yl)amino]propan-2-ol

MS (ESI): mass calcd. for C₁₃H₂₂N₄O, 250.35 m/z found, 251.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.63 (d, J=7.8 Hz, 1H), 6.64 (dd, J=7.8 Hz, J =2.4Hz, 1H), 6.23 (d, J=1.8 Hz, 1H), 3.86-3.82 (m, 4H), 3.55 (s, 3H),3.39-3.36 (m, 4H), 1.28 (s, 6H).

Example 291N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₂₁ H ₃₂ N₄, 340.52 m/z found, 341.3 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD): 7.50 (d, J=7.5 Hz, 1H), 6.31 (dd, J=2.1 Hz, 7.2Hz, 1 H), 5.71 (s, 1H), 4.43 (t, J=6.0 Hz, 1 H), 3.93-3.68 (m, 3H),3.45-3.20 (m, 6H), 2.44-2.25 (m, 3H), 2.06-1.90 (m, 6H), 1.57-1.52 (m,1H), 1.52 (s, 3H), 1.19 (s, 3H), 0.93 (d, J=9.6 Hz, 1H).

Example 292 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine

MS (ESI): mass calcd. for C₁₄H₂₂N₄, 246.36 m/z found, 247.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.25 (br, s, 1H), 8.57 (br, s, 3H), 7.95 (d, J=6.9 Hz, 1H), 7.64 (t, J=6.3 Hz, 1H), 6.27 (d, J=6.6 Hz, 1H), 5.68 (s, 1H), 4.04-3.87 (m, 3H), 3.66-3.40 (m, 4H), 2.38-2.18 (m, 2H), 2.02-1.96(m, 2H), 1.70-1.24 (m, 6H).

Example 293N-(2,2-Dimethylpropyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₂₆N₄, 274.41 m/z found, 275.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.57 (d, J=7.5 Hz, 1H), 6.38 (dd, J=2.4 Hz, 7.5Hz, 1H), 5.90 (d, J=2.4 Hz, 1H), 4.51-4.48 (m, 1H), 4.00-3.75 (m, 3H),3.52-3.37 (m, 4H), 3.11 (s, 2H), 2.40-2.34 (m, 1H), 2.12-2.08 (m, 1H),1.03 (s, 9H).

Example 294443-(Methylamino)azetidin-1-yl]-N-(2-phenylethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₇H₂₂N₄, 282.39 m/z found, 283.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.38 (br, s, 1H), 10.08 (br, s, 2H), 7.83-7.63(m, 2H), 7.32-7.22 (m, 5H), 6.09 (d, J=6.9 Hz, 1H), 5.59 (s, 1H), 5.03(br, s, 2H), 4.33-3.98 (m, 5H), 3.52-3.46 (m, 2H), 2.87 (t., J=7.2 Hz,2H), 2.54 (s, 3H).

Example 295N-(4-Fluorobenzyl)-443-(methylamino)azetidin-1-yl]pyridin-2-amine

MS (ESI): mass calcd. for C₁₆H₁₉FN₄, 286.36 m/z found, 287.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆): 12.55 (br, s, 1 H), 9.99 (br, s, 2H), 8.28 (br,s, 1H), 7.68 (t, J=6.3 Hz, 1H), 7.45-7.41 (m, 2H), 7.24-7.18 (m, 2H),6.11 (d, J=5.7 Hz, 1H), 5.63 (s, 1H), 4.51 (d, 5.7 Hz, 2H), 4.21-4.14(m, 7H), 2.53 (s, 3H).

Example 296Adamantan-1-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine

MS (ESI): mass calcd. for C₂₁H₃₀N₄, 338.5 m/z found, 339.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.54 (d, J=7.2 Hz, 1H), 6.32 (d, J=7.5 Hz, 1H),5.83 (s, 1H), 4.44 (t, J=6.6 Hz, 1H), 3.91-3.68 (m, 4H), 3.46- 3.40 (m,3H), 2.34-2.28 (m, 1H), 2.20-2.00 (m, 1H), 2.13 (s, 3H), 2.06 (s, 6H),1.75 (s, 6H).

Example 297443-(Methylamino)azetidin-1-yl]-N-(pyridin-2-ylmethyppyridin-2-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.76 (d, J=5.4Hz, 1H), 8.55 (t, J=7.5 Hz, 1H),8.03 (d, J=7.8 Hz, 1H), 7.96 (t, J=6.6 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H),6.18 (d, J=6.9 Hz, 1H), 5.74 (s, 1H), 5.01 (s, 2H), 4.41 (br, s, 2H),4.25-4.21 (m, 3H), 2.65 (s, 3H).

Example 2985-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyppyridazin-3-amine

3,4,5-trichloropyridazine. A solution of 4,5-dichloropyridazin-3(2H)-one(2 g, 12 mmol) in 20 mL of phosphoryl trichloride was heated to refluxfor 2 hrs. The solvent was removed under reduce pressure. The residuewas poured into water with stirring and extracted with dicloromathene(50 mL*3). The organic layer was washed with brine, dried over Na₂SO₄,evaporated to give the crude product (U.S. Pat. Appl. Publ. US 6800758(Egis Gyogyszergyar Rt., Hung., Oct. 5, 2004). The crude product wasrecrystallized with acetone/water to give the product (2 g, 83%). ¹HNMR(300 MHz, CDCl₃): 9.09 (s, 1 H); LC-MS: m/z=182.9 [M+H]⁺.

(R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate.To a stirred solution of 3,4,5-trichloropyridazine (500 mg, 5.5mmol) andDIPEA (1 mL) in propan-2-ol (5 mL) was added (R)-tert-butylpyrrolidin-3- ylcarbamate (508 mg, 5.5 mmol) at ambient temperature. Thesolvent was removed and the residue was purified by columnchromatography (petroleum ether/ethyl acetate=2/1, v/v) to afford thetitle desired product (500mg, 55%).¹H NMR (300 MHz, CDCl₃): 8.42 (s,1H), 5.06 (br s, 1H), 4.36 (br s, 1H), 4.05-3.99 (m, 1 H), 3.90-3.66 (m,3H), 2.28-2.23 (m, 1H), 2.09-2.07 (m, 1H), 1.48 (s, 9H); LC-MS:m/z=333.1 [M+H]⁺

(R)-tert-butyl 1-(5-chloro-6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate. A mixture of 100 mg of (R)-tert-butyl1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate and2-methoxyethanamine (1mL) was heated at 145° C. for 40 min in microwave.The mixture was concentrated and the crude was purified by silica gelchromatography (EA/PE=1/4, v/v) to give the title product (50 mg, 45%).LC-MS: m/z=372.2 [M+H]⁺.

(R)-tert-butyl1-(6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate. Tothe mixture of (R)-tert-butyl1-(5-chloro-6-(2-methoxyethylamino)pyridazin-4-yl)pyrrolidin-3-ylcarbamate (50 mg, 0.13 mmol) and ammonium formate(HCOONH₄) (85 mg, 1.3 mmol) in MeOH (2 mL) was added 10% Pd/C (20 mg).The resulting mixture was refluxed for 2 hours. The reaction was allowedto cool to room temperature and filtered. The filtrate was concentrated,diluted with EA (20 mL) and washed with brine (10 mL*2). The combinedorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified by pre-TLC (PE/EA=⅕, v/v) to give the product as oil (20 mg,44%). ¹H NMR (300 MHz, CDCl₃): 8.02 (s, 1H), 5.46 (s, 1H), 5.10-5.08 (m,1H), 4.91 (br s, 1H), 4.33-4.26 (m, 1H), 3.59-3.51 (m, 4H), 3.40-3.35(m, 4H), 3.19-3.15 (m, 1H), 2.28-2.19 (m, 1H), 1.99-1.97 (m, 1H), 1.44(s, 9H); LC-MS: m/z =338.2 [M+H]⁺.

(R)-5-(3-aminopyrrolidin-1-yl)-N-(2-methoxyethyl)pyridazin-3-aminedihydrochloride. To solution of (R)-tert-butyl1-(6-(2-methoxyethylamino)pyridazin-4-yl) pyrrolidin-3-ylcarbamate (198mg, 0.59 mmol) in MeOH (3 mL) was added 7N HCl in ether (10 mL). Thereaction was stirred at room temperature for 16 hours. The reaction wasconcentrated under reduced pressure to give the desired product as alight yellow solid (94.5 mg, 52%). ¹H NMR (300 MHz, CD₃OD): 8.14 (s,1H), 6.12 (s, 1H), 4.15-3.54 (m, 9H), 3.40 (s, 3H), 2.57-2.52 (m, 1H),2.32-2.30 (m, 1 H); mass calcd. for C₁₁H₁₉N₅O, 237.31, LC-MS: m/z=238.2[M+H]⁺, t_(R)=0.3 min; HPLC: 99% (214 nm), 95% (254 nm), t_(R)=4.4 min.

The compounds in Example 299 through Example 310 were prepared usingmethods analogous to those described in Example 298.

Example 299543-(Methylamino)azetidin-1-yl]-N-(4,4,4-trifluorobutyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H-₁₈F₃N₅, 289.31 m/z found, 290.1 [M+H]⁺.¹H NMR (300 MHz, CD₃OD): 7.84 (d, J=2.1 Hz, 1H), 5.88 (d, J=2.4 Hz, 1H),4.60-4.40 (m, 2H), 4.31-4.22 (m, 3H), 3.31 (t, J=6.9 Hz, 2H), 2.69 (s,3H), 2.26-2.18 (m, 2H), 1.86-1.79 (m, 2H).

Example 300N⁵-(2-Aminoethyl)-N³-(2,2-dimethylpropyl)-N⁵-methylpyridazine-3,5-diamine

MS (ESI): mass calcd. for C₁₂H₂₃N₅, 237.35 m/z found, 238.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.4 Hz, 1H), 6.29 (s, 1H), 3.79 (t,J=6.6 Hz, 2H), 3.21-3.08 (m, 7H), 0.94 (s, 9H).

Example 301543-(Methylamino)azetidin-1-yl]-N-R1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₈H₂₉N₅, 315.47 m/z found, 316.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.94 (s, 1H), 5.98 (s, 1H), 4.70-4.30 (m, 5H),4.02-3.99 (m, 1H), 2.81(s, 3H), 2.80-2.70 (m, 1H), 2.60-2.50 (m, 1H),2.16-1.72 (m, 4H), 1.40-1.30 (m, 1H), 1.32 (s, 3H), 1.20 (d, J=7.2 Hz,3H), 1.09 (s, 3H).

Example 302N⁵-(2-Amino-ethyl)-N³-bicyclo[2.2.1]hept-2-yl-N⁵-methyl-pyridazine-3,5-diamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.4 Hz, 1H), 6.08 (d, J=2.1 Hz, 1H),3.77 (t, J=6.9 Hz, 2H), 3.44-3.42 (m, 1 H), 3.14 (t, J=6.9 Hz, 2H), 3.09(s, 3H), 2.24 (d, J=21 Hz, 2H), 1.88-1.81 (m, 1H), 1.58-1.14 (m, 7H).

Example 303N⁵-(2-Aminoethyl)-N³-(cyclopentylmethyl)-N⁵-methylpyridazine-3,5-diamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.4 Hz, 1H), 6.15 (s, 1H), 3.78 (t,J=6.9 Hz, 2H), 3.21-3.10 (m, 7H), 1.81-1.53 (m, 7H), 1.25-1.20 (m, 2H).

Example 3045-[(3S)-3-Aminopyrrolidin-1-yl]-N-(bicyclo[2.2.1]hept-2-ylmethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.18 (d, J=2.1 Hz, 1H), 6.12 (d, J=2.1 Hz, 1H),4.20-3.50 (m, 5H), 3.40-3.00 (m, 2H), 2.64-2.57 (m, 1H), 2.40-2.20 (m,3H), 1.96-0.82 (m, 9H).

Example 3053-({5-[(3aR,6aR)-Hexahydropyrrolo[3,4-1D]pyrrol-5(1H)-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.35 m/z found, 264.2 [M-F1-1]⁺.¹H NMR (300 MHz, CD₃OD): 8.11 (s, 1H), 6.08 (s, 1H), 4.52-4.48 (m, 1 H),4.05-3.84 (m, 2H), 3.76-3.66 (m, 2H), 3.56-3.41 (m, 5H), 2.39-2.33 (m,1H), 2.11-2.09 (m, 1H), 1.92-1.83 (m, 2H).

Example 3065-(3-Aminoazetidin-1-yl)-N-{[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₇N₅, 301.44 m/z found, 302.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.79 (d, J=2.7 Hz, 1H), 5.78 (s, 1H), 4.60-4.40(m, 2H), 4.30-4.10 (m, 3H), 3.30-3.10 (m, 2H), 2.40-2.20 (m, 2H),1.94-1.85 (m, 5H), 1.50-1.40 (m, 1H), 1.14 (s, 3H), 0.99 (s, 3H), 0.88(d, J=9.9 Hz, 1H).

Example 3075-(1,4-Diazepan-1-yl)-N-(2,2-dimethylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.39 m/z found, 264.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (d, J=2.1 Hz, 1H), 6.41 (d, J=2.1Hz, 1H),4.04-4.03 (m, 2H), 3.81-3.79 (m, 2H), 3.53-3.49 (m, 2H), 3.43-3.41 (m,2H), 3.20 (s, 2H), 2.30-2.28 (m, 2H), 1.06 (s, 9H).

Example 308N-Bicyclo[2.2.1]hept-2-yl-5-(1,4-diazepan-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.35 (s, 1H), 6.22 (s, 1H), 4.03-4.02 (m, 2H),3.79-3.77 (m, 2H), 3.55-3.49 (m, 3H), 3.42-3.37 (m, 3H), 2.32-2.28 (m,3H), 1.99-1.92 (m, 1H), 1.70-1.62 (m, 3H), 1.59-1.22 (m, 4H).

Example 309 N-Cyclopropyl-5-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₁₉N₅, 245.33 m/z found, 246.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.17 (d, J=2.4 Hz, 1H), 6.07 (d, J=2.1 Hz, 1H),4.53-4.49 (m, 1H), 3.99-3.40 (m, 7H), 2.67-2.62 (m, 1H), 2.41-2.37 (m,1H), 2.14-2.08 (m, 1H), 1.01-0.95 (m, 2H), 0.71-0.66 (m, 2H).

Example 310 N-Butyl-5-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (d, J=2.4 Hz, 1H), 6.06 (d, J=2.1 Hz, 1H),4.54-4.50 (m, 1H), 4.08-3.40 (m, 7H), 3.33-3.31 (m, 2H), 2.41-2.34 (m,1H), 2.14-2.09 (m, 1H), 1.73-1.63 (m, 2H), 1.51-1.44 (m, 2H), 1.00 (t,J=7.5 Hz, 3H).

Example 311 N-(Cyclopentylmethyl)-4-piperazin-1-ylpyridin-2-amine

The titled compound was prepared in a manner analogous to Example 254.MS (ESI): mass calcd. for C₁₅H₂₄N₄, 260.39 m/z found, 261.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.55 (d, J=7.5 Hz, 1H), 6.59 (dd, J=7.5 Hz, J =1.8Hz, 1H), 6.09 (d. J=1.8 Hz, 1 H), 3.79 (t, J=5.7 Hz, 4H), 3.33 (t, J=5.1Hz, 4H), 3.17 (d, J=7.5 Hz, 2H), 2.20-2.15 (m, 1H), 1.87-1.81 (m, 2H),1.66-1.58 (m, 4H), 1.29-1.23 (m, 2H).

The compounds in Example 312 through Example 371 were prepared usingmethods analogous to those described in Example 298.

Example 3125-[(3R)-3-Aminopyrrolidin-1-yl]-N-(bicyclo[2.2.1]hept-2-ylmethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.3 [M+H]⁺. ¹H

NMR (300 MHz, CD₃OD): 8.18 (d, J=2.1 Hz, 1H), 6.10 (d, J=2.1 Hz, 1H),4.20-3.50 (m, 5H), 3.40-3.00 (m, 2H), 2.64-2.57 (m, 1H), 2.40-2.20 (m,3H), 2.00-0.82 (m, 9H).

Example 3133-({5-[(3R)-3-Aminopyrrolidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (br, s, 1H), 6.06 (s, 1H), 4.14 (s, 1H),3.84-3.54 (m, 6H), 3.45-3.41 (m, 2H), 2.55-2.51 (m, 1H), 2.28 (br, s,1H), 1.88 (t, J=6.6 Hz, 2H).

Example 314 3-[(5-Piperazin-1-ylpyridazin-3-yl)amino]propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹H

NMR (300 MHz, CD₃OD): 8.37 (s, 1 H), 6.42 (br, s, 1H), 3.89 (br, s, 4H),3.69 (t, J=5.4 Hz, 2H), 3.47-3.47 (m, 6H), 1.89 (t, J=6.3 Hz, 2H).

Example 315 N-Cyclopropyl-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.29 m/z found, 220.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.38 (s, 1H), 6.37 (s, 1H), 3.87-3.85 (m, 4H),3.37-3.36 (m, 4H), 2.62-2.60 (br, s, 1H), 0.97-0.91 (m, 2H), 0.65 (br,s, 2H).

Example 316 N-(Cyclopentylmethyl)-5-(1,4-diazepan-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (d, J=2.4Hz, 1H), 6.39 (d, J=2.4 Hz, 1H),4.04-4.02 (m, 2H), 3.80-3.78 (m, 2H), 3.52-3.49 (m, 2H), 3.42-3.37 (m,2H), 3.28 (d, J=7.5 Hz, 2H), 2.30-2.22 (m, 3H), 1.93-1.91 (m, 2H),1.73-1.65 (m, 4H), 1.34-1.32 (m, 2H).

Example 3175-[(35)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (s, 1H), 6.08 (s, 1H), 4.17-4.15 (m, 1H),4.10-3.54 (m, 4H), 3.27 (d, J=7.2 Hz, 2H), 2.60-2.51 (m, 1 H), 2.29-2.20(m, 2H), 1.92-1.90 (m, 2H), 1.73-1.65 (m, 4H), 1.36-1.32 (m, 2H).

Example 318 5-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.07 (d, J=2.4 Hz, 1H), 6.04 (d, J=2.1 Hz, 1H),4.48-4.44 (m, 1H), 4.06-3.77 (m, 3H), 3.53-3.26 (m, 4H), 3.10 (d, J=7.2Hz, 2H), 2.36-2.29 (m, 1H), 2.09-0.97 (m, 2H), 0.98 (d, J=6.9 Hz, 6H).

Example 319543-(Methylamino)azetidin-1-yl]-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁ N₅, 235.33 m/z found, 236.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.94 (d, J=2.1 Hz, 1H), 5.98 (s, 1H), 4.70-4.34(m, 5H), 3.17 (d, J=7.2 Hz, 2H), 2.81 (s, 3H), 1.99-1.93 (m, 1H), 1.05(d, J=6.6 Hz, 6H).

Example 320N-(2-Methoxyethyl)-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.94 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 4.70-4.35(m, 5H), 3.65-3.62 (m, 2H), 3.56-3.53 (m, 2H), 3.42 (s, 3H), 2.81 (s,3H).

Example 321 5-[(3R)-3-Aminopyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.09(s, 1H), 7.39-7.29 (m, 5H), 5.95 (s, 1H), 4.10(br, s, 1H), 3.98-3.53 (m, 5H), 2.54-2.48 (m, 1H), 2.26-2.22 (m, 1H),1.61 (d, J=6.9 Hz, 3H).

Example 3225-(3-Aminoazetidin-1-yl)-N-bicyclo[2.2.1]hept-2-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₁ N₅, 259.36 m/z found, 260.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.89 (d, J=1.5 Hz, 1H), 5.87 (s, 1H), 4.59 (br, s,2H), 4.33 (br, s, 3H), 3.50-3.48 (m, 1 H), 2.35-2.27 (m, 2H), 1.94-1.87(m, 1H), 1.67-1.18 (m, 4H).

Example 3235-(3-Aminoazetidin-1-yl)-N-(2,2-dimethylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁ N₅, 235.33 m/z found, 236.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.90 (s, 1 H), 6.06 (s, 1H), 4.62 (br s, 2H), 4.35(br s, 3H), 3.15 (s, 2H), 1.03 (s, 9H).

Example 324N-(2,2-Dimethylpropyl)-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.95 (d, J=2.4 Hz, 1H), 6.10 (d, J=2.1 Hz, 1H),4.70-4.36 (m, 5H), 3.19 (s, 2H), 2.83 (s, 3H), 1.07 (s, 9H).

Example 325N-Cyclohexyl-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.84 (s, 1H), 5.86 (s, 1H), 4.53 (br, s, 2H),4.30-4.26 (m, 3H), 3.57-3.49 (m, 1H), 2.73 (d, J=3.3 Hz, 3H), 1.96-1.92(m, 2H), 1.79-1.63 (m, 3H), 1.44-1.11 (m, 5H).

Example 326 5-(3-Aminoazetidin-1-yl)-N-cyclopentylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.88 (s, 1 H), 5.86 (s, 1H), 4.58 (br s, 2H),4.40-4.20 (m, 3H), 4.00-3.96 (m, 1H), 2.09-2.04 (m, 2H), 1.80-1.58 (m,6H).

Example 327N-(Cyclopropylmethyl)-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.87 (d, J=2.4 Hz, 1H), 5.91 (d, J=2.4 Hz, 1H),4.56 (br, s, 2H), 4.36-4.26 (m, 3H), 3.16 (d, J=7.2 Hz, 2H), 1.15-1.01(m, 1 H), 0.66-0.60 (m, 2H), 0.34-0.29 (m, 2H).

Example 328 5-(3-Aminoazetidin-1-yl)-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.31 m/z found, 222.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.90 (s, 1H), 5.94 (s, 1H), 4.70-4.30 (m, 5H),3.13 (d, J=6.9 Hz, 2H), 1.93-1.92 (m, 1H), 1.02 (d, J=6.3 Hz, 6H).

Example 329 5-(3-Aminoazetidin-1-yl)-N-benzylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₁₇N₅, 255.33 m/z found, 256.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.88 (d, J=2.4 Hz, 2H), 7.38-7.29 (m, 5H), 5.90(d, J=2.4 Hz, 1H), 4.53 (s, 4H), 4.36-4.30 (m, 3H).

Example 330 N-Benzyl-5-[3-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.80 (br, s, 1H), 7.27 (br, s, 5H), 5.82 (s, 1H),4.44 (s, 4H), 4.19 (br, 3H), 2.66 (s, 3H).

Example 331N-Bicyclo[2.2.1]hept-2-yl-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.88 (s, 1 H), 5.82 (d, J=2.7 Hz, 1H), 4.56 (br,s, 2H), 4.35-4.23 (m, 3H), 3.48-3.46 (m, 1H), 2.36 (s, 3H), 2.28-2.27(m, 2H), 1.94-1.87 (m, 1H), 1.63-1.17 (m, 7H).

Example 332N-Cyclopentyl-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.35 m/z found, 248.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.78 (br, s, 1H), 5.77 (br, s, 1H), 4.46 (br, s,2H), 4.25-4.21 (m, 3H), 3.88-3.86 (m, 1H), 2.67 (s, 3H), 1.99-1.95 (m,2H), 1.70-1.48 (m, 6H).

Example 333 5-(3-Aminoazetidin-1-yl)-N-cyclopropylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₀H₁₅N₅, 205.26 m/z found, 206.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.95 (d, J=2.4 Hz, 1H), 5.92 (d, J=1.8 Hz, 1H),4.60 (br, s, 2H), 4.37-4.31 (m, 3H), 2.64-2.59 (m, 1H), 0.99-0.93 (m,2H), 0.69-0.64 (m, 2H).

Example 3343-({543-(Methylamino)azetidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.90 (d. J=2.7 Hz, 1H), 5.97 (d, J=2.4 Hz, 1H),4.58 (br, s, 2H), 4.39-4.31 (m, 3H), 3.68 (t, J=6.0 Hz, 2H), 3.42 (t,J=6.9 Hz, 2H), 2.77 (s, 3H), 1.91-1.82 (m, 2H).

Example 335 5-(3-Aminoazetidin-1-yl)-N-(2-methoxyethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.28 m/z found, 224.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.94 (d, J=2.4 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H),4.64 (br s, 2H), 4.41-4.36 (m, 3H), 3.66-3.63 (m, 2H), 3.56-3.53 (m,2H), 3.42 (s, 3H).

Example 3365-[(35)-3-Aminopyrrolidin-1-yl]-N-cyclopropylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.29 m/z found, 220.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (d, J=2.4 Hz, 1H), 6.04 (d, J=2.1 Hz, 1H),4.13-3.53 (m, 5H), 2.67-2.51 (m, 2H), 2.31-2.24 (m, 1H), 1.00-0.94 (m,2H), 0.70-0.65 (m, 2H).

Example 3375-[(3R)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.34 m/z found, 271.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.80 (d, J=5.7 Hz, 1H), 8.53 (t, J=7.8 Hz, 1H),8.20 (s, 1H), 8.05-7.93 (m, 2H), 6.24 (s, 1H), 5.01 (s, 2H), 4.09 (br,s, 1H), 3.82-3.60 (m, 4H), 2.53-2.46 (m, 1H), 2.24-2.22 (m, 1H).

Example 3383-({5-[(35)-3-Aminopyrrolidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.31 m/z found, 238.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (d, J=2.1 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H),4.13-3.53 (m, 7H), 3.43 (t, J=6.9 Hz, 2H), 2.58-2.48 (m, 1H), 2.30-2.26(m, 1 H), 1.92-1.84 (m, 2H).

Example 3395-[(35)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁ N₅, 235.33 m/z found, 236.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (s, 1H), 6.05 (s, 1H), 4.14-3.16 (m, 5H),3.15 (d, J=6.9 Hz, 2H), 2.58-2.52 (m, 1H), 2.28-2.20 (m, 1H), 2.00-1.91(m, 1H), 0.93 (d, J=6.9 Hz, 6H).

Example 340 5-[(3R)-3-Aminopyrrolidin-1-yl]-N-benzylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.09 (s, 1H), 7.35-7.29 (m, 5H), 5.98 (s, 1 H),4.52 (s, 2H), 4.07 (br, s, 1H), 3.78-3.41 (m, 4H), 2.52-2.45 (m, 1H),2.24-2.20 (m, 1H).

Example 3415-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methoxybenzyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅O, 299.38 m/z found, 300.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (s, 1 H), 7.34 (d, J=8.7 Hz, 2H), 6.96 (d,J=8.7 Hz, 2H), 6.03 (d, J=2.1 Hz, 1H), 4.50 (s, 2H), 4.14-3.56 (m, 5H),3.81 (s, 3H), 2.59-2.52 (m, 1H), 2.31-2.27 (m, 1H).

Example 3425-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₁₈FN₅, 287.34 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.1 Hz, 1H), 7.50-7.45 (m, 2H),7.20-7.14 (m, 2H), 6.08 (d, J=2.1 Hz, 1H), 4.59 (s, 2H), 4.17-3.58 (m,5H), 2.61-2.52 (m, 1H), 2.36-2.30 (m, 1H).

Example 3435-[(3R)-3-Aminopyrrolidin-1-yl]-N-(4-methylbenzyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.17 (d, J=2.7 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H),7.25 (d, J=7.8 Hz, 2H), 6.08 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 4.17-3.58(m, 5H), 2.63-2.51 (m, 1H), 2.40 (s, 3H), 2.37-2.26 (m, 1H).

Example 344 N-(4-MethylbenzyI)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.29 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H),7.11 (d, J=8.1 Hz, 2H), 6.29 (d, J=2.4 Hz, 1H), 4.42 (s, 2H), 3.80-3.76(m, 4H), 3.32-3.29 (m, 4H), 2.24 (s, 3H).

Example 345 N-Cyclopentyl-5-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.38 m/z found, 274.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (s, 1 H), 6.06 (br s, 1H), 4.52 (m, 1H),4.06-3.40 (m, 8H), 2.39-2.35 (m, 1H), 2.10-1.80 (m, 3H), 1.82-1.62 (m,6H).

Example 346 N-(4-Fluorobenzyl)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₁₈FN₅, 287.34 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.41 (d, J=2.4 Hz, 1H), 7.46-7.42 (m, 2H),7.17-7.12 (m, 2H), 6.42 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.92-3.88 (m,4H), 3.43-3.40 (m, 4H)

Example 347 N-(4-MethoxybenzyI)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅O, 299.38 m/z found, 300.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.39 (s, 1 H), 7.33 (d, J=7.2 Hz, 2H), 6.95 (d,J=7.2 Hz, 2H), 6.38 (s, 1H), 4.49 (s, 2H), 3.87 (m, 4H), 3.79 (s, 3H),3.42-3.39 (m, 4H).

Example 348 N-Benzyl-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35 m/z found, 270.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.41 (d, J=2.7 Hz, 1H), 7.42-7.35 (m, 5H), 6.41(d, J=2.7 Hz, 1H), 4.58 (s, 2H), 3.95-3.87 (m, 4H), 3.43-3.36 (m, 4H).

Example 349 N-[(1R)-1-PhenylethyI]-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (s, 1H), 7.41-7.31 (m, 5H), 6.37 (s, 1H),4.95-4.84 (m, 1 H), 3.85 (m, 4H), 3.41-3.38 (m, 4H), 1.63 (d, J=6.9 Hz,3H).

Example 3503-({5-[(3R)-3-Aminopyrrolidin-1-yl]pyridazin-3-yl}amino)-2,2-dimethylpropan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 280.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (s, 1H), 6.21 (s, 1H), 4.32-3.58 (m, 5H),3.39 (s, 2H), 3.28 (s, 2H), 2.62-2.52 (m, 1H), 2.32-2.30 (m, 1H), 1.03(s, 6H).

Example 351N-Cyclopropyl-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.29 m/z found, 220.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.95 (d, J=2.1 Hz, 1H), 5.94 (s, 1H), 4.58 (br, s,2H), 4.39-4.31 (m, 3H), 2.77 (s, 3H), 2.64-2.60 (m, 1H), 0.99-0.93 (m,2H), 0.69-0.67 (m, 2H).

Example 352543-(Methylamino)azetidin-1-yl]-N-(pyridin-2-ylmethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.34 m/z found, 271.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.82 (d, J =4.8 Hz, 1H), 8.60 (s, 1H), 8.08-7.99(m, 3H), 6.20 (s, 1H), 5.07 (br, s, 2H), 4.59-4.43 (m, 4H), 4.25 (br, s,1H), 2.73 (d, J=10.2 Hz, 3H).

Example 3535-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.33 m/z found, 236.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (s, 1H), 6.05 (s, 1H), 4.13-3.59 (m, 5H),3.15 (d, J=6.9 Hz, 2H), 2.58-2.51 (m, 1H), 2.40-2.20 (m, 1H), 1.99-1.91(m, 1H), 1.03 (d, J=6.6 Hz, 6H).

Example 354 N-Cyclopentyl-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.35 m/z found, 248.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.32 (d, J=2.4 Hz, 1H), 6.34 (d, J=2.1 Hz, 1H),4.02-3.94 (m, 1H), 3.86-3.83 (m, 4H), 3.39-3.35 (m, 4H), 2.08-1.99 (m,2H), 1.79-1.55 (m, 6H).

Example 355 N-Cyclohexyl-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.33 (d,J=2.7 Hz, 1H), 6.31 (d, J=2.7 Hz, 1H),3.84 (t, J=5.1 Hz, 4H), 3.55 (br, 1H), 3.40 (t, J=5.1 Hz, 4H), 2.01-1.80(m, 4H), 1.62-1.75 (m, 1H), 1.48-1.28 (m, 5H).

Example 356 N-Butyl-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁ N₅, 235.33 m/z found, 236.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (s, 1 H), 6.37 (s, 1H), 3.88 (t, J=5.4 Hz,4H), 3.41 (t, J=5.4 Hz, 4H), 3.35-3.29 (m, 2H), 1.69-1.64 (m, 2H),1.50-1.43 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).

Example 357 N-(2,2-DimethylpropyI)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (d, J=2.7 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H),3.88 (t, J=5.1 Hz, 4H), 3.41 (t, J=5.1 Hz, 4H), 3.17 (s, 2H), 1.03 (s,9H).

Example 3585-(3-Aminoazetidin-1-yl)-N-(cyclopentylmethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₁ N₅, 247.35 m/z found, 248.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.77 (s, 1 H), 5.80 (d, J=2.1 Hz, 1H), 4.48 (br s,2H), 4.26-4.20 (m, 3H), 3.12 (d, J=7.2 Hz, 2H), 2.15-2.05 (m, 1H),1.78-1.52 (m, 6H), 1.22-1.16 (m, 2H).

Example 3595-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.00 (s, 1 H), 5.91 (d, J=2.4 Hz, 1H), 4.03-4.00(m, 1H), 3.90-3.40 (m, 4H), 3.13 (d, J=7.5 Hz, 2H), 2.47-2.40 (m, 1H),2.23-2.07 (m, 2H), 1.81-1.52 (m, 6H), 1.23-1.17 (m, 2H).

Example 360N-(Cyclopentylmethyl)-5-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.00 (s, 1H), 5.92 (s, 1H), 4.41-4.36 (m, 1H),3.91-3.70 (m, 3H), 3.44-3.27 (m, 4H), 3.13 (d, J=7.5 Hz, 2H), 2.31-2.23(m, 1H), 2.14-2.01 (m, 2H), 1.79-1.52 (m, 6H), 1.23-1.17 (m, 2H).

Example 361 N-(Cyclopropylmethyl)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.36 (s, 1 H), 6.40 (s, 1H), 3.89 (t, J=7.8 Hz,4H), 3.41 (t, J=4.8 Hz, 4H), 3.20 (d, J=6.9 Hz, 2H), 1.17-1.15 (m, 1H),0.64 (d, J=8.1 Hz, 2H), 0.34 (d, J=4.8 Hz, 2H).

Example 362 N-(2-Phenylethyl)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.33 (d, J=2.1 Hz, 1H), 7.30-7.22 (m, 5H), 6.29(d, J=2.1 Hz, 1H), 3.86 (t, J=5.4 Hz, 4H), 3.63 (t, J=6.9 Hz, 2H),3.41-3.34 (m, 4H), 2.98 (t, J=6.9 Hz, 2H).

Example 363 N-(Cyclopentylmethyl)-5-piperazin-1-ylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.33 (s, 1H), 6.38 (s, 1H), 3.86 (s, 4H),3.50-3.23 (s, 6H), 2.24-2.17 (m, 1H), 1.86 (br, s, 2H), 1.65 (br, s,4H), 1.29 (br, s, 2H).

Example 3645-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.09 (s, 1H), 7.29-7.23 (m, 5H), 5.96 (s, 1H),4.13-3.64 (m, 5H), 3.62 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.6 Hz, 2H), 2.53(m, 1H), 2.28 (m, 1H).

Example 3655-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.3 [M+H]⁺. ¹HNfMR (300 MHz, CD₃OD): 8.11 (s, 1H), 6.03 (s, 1H), 4.14-3.56 (m, 6H),2.58-2.51 (m, 1H), 2.40-2.20 (m, 1H), 1.85-1.68 (m, 5H), 1.54-1.26 (m,5H).

Example 3662,2-Dimethyl-3-[(5-piperazin-1-ylpyridazin-3-yl)amino]propan-1-ol

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.36 m/z found, 266.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.27 (d, J=1.2Hz, 1H), 6.46 (d, J=2.4Hz, 1H),3.81-3.79 (m, 4H), 3.33-3.32 (m, 4H), 3.26 (s, 2H), 3.16 (s, 2H), 1.02(s, 6H).

Example 367 5-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.33 m/z found, 236.1 [M+H]⁺. ¹H

NMR (300 MHz, CD₃OD): 8.02 (s, 1 H), 5.92 (d, J=2.1 Hz, 1H), 4.04-3.44(m, 5H), 3.24-3.20 (m, 2H), 2.48-2.41 (m, 1H), 2.21-2.14 (m, 1H),1.62-1.52 (m, 2H), 1.41-1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).

Example 3685-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.35 m/z found, 248.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (s, 1H), 6.04 (s, 1H), 4.15-3.36 (m, 6H),2.56-2.52 (m, 1H), 2.31 (m, 1H), 2.09 (br s, 2H), 1.80-1.62 (m, 6H).

Example 3695-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopropylmethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (br, s, 1H), 6.04 (br, s, 1H), 4.14 (br, s,1H), 3.92-3.73 (m, 4H), 3.19 (d, J=6.6 Hz, 2H), 2.58-2.51 (m, 1H),2.29-2.27 (m, 1H), 1.15 (br, s, 1H), 0.66-0.64 (m, 2H), 0.35-0.34 (m,2H).

Example 370N-(Cyclopentylmethyl)-543-(methylamino)azetidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 7.89 (d, J=2.1Hz, 1H), 5.95 (d, J=2.1 Hz, 1H),4.62-4.57 (m, 2H), 4.40-4.30 (m, 3H), 3.34-3.32 (m, 2H), 2.77 (s, 3H),2.23-2.18 (m, 1H), 1.88-1.86 (m, 2H), 1.66-1.64 (m, 4H), 1.30-1.28 (m,2H).

Example 3715-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2,2-dimethylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (s, 1H), 6.15 (s, 1H), 4.13-3.50 (m, 5H),3.15 (s, 2H), 2.57-2.50 (m, 1H), 2.40-2.20 (m, 1H), 1.02 (s, 9H).

Example 3725-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyridazin-3-amine

3,4,5-trichloropyridazine. A solution of 4,5-dichloropyridazin-3(2H)-one(2 g, 12 mmol) in 20 mL of phosphoryl trichloride was heated to refluxfor 2 hrs. The solvent was removed under reduce pressure. The residuewas poured into water with stirring and extracted with dicloromathene(50 mL*3). The organic layer was washed with brine, dried over Na₂SO₄,evaporated to give the crude product. The crude product wasrecrystallized with acetone/water to give the product (2 g, 89%). ¹H NMR(300 MHz, CDCl₃): 9.09 (s, 1H); LC-MS: m/z=182.9[M+F]⁺.

(R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate.To a stirred solution of 3,4,5-trichloropyridazine (500 mg, 2.7mmol) andDIPEA (1 mL) in propan-2-ol (5 mL) was added (R)-tert-butylpyrrolidin-3- ylcarbamate (508 mg, 2.7 mmol) at ambient temperature (18h). The solvent was removed and the residue was purified by columnchromatography (Petroleum Ether/Ethyl Acetate=2/1, v/v) to afford thetitle desired product (500 mg, 55%). ¹H NMR (300 MHz, CDCl₃): 8.42 (s,1H), 5.06 (br s, 1H), 4.36 (br s, 1H), 4.05-3.99 (m, 1 H), 3.90-3.66 (m,3H), 2.28-2.23 (m, 1H), 2.09-2.07 (m, 1H), 1.48 (s, 9H); LC-MS: m/z=333.1 [M+H]⁺

(R)-tert-butyl 1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate. NaH (60% in oil, 0.72 g, 18.0 mmol) was suspended in 40 mL ofanhydrous DMF. A solution of (R)-tert-butyl1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-ylcarbamate (5 g, 15 mmol) inanhydrous DMF (40 mL) was added at −5° C. After 40 min, CH₃l (2.55 g, 18mmol) was added. Then the resulting mixture was stirred at ambienttemperature for 2 hours. The reaction was monitored by LC-MS. Water (100mL) was added and the mixture was extracted with EtOAc (3×200 mL). Theorganic layer was washed with brine (3×200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel (Petroleum Ether/EtOAc=5/1, v/v) to afford the desired product (4.2g, 80%).¹H NMR (300 MHz, CDCl₃) δ 8.39 (s, 1H), 4.77-4.76 (m, 1H),3.86-3.62 (m, 4H), 2.85 (s, 3H), 2.18-2.11 (m, 2H), 1.46 (s, 9H); LC-MS:m/z=347.1[M+H]⁺.

(R)-tert-butyl1-(5-chloro-6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate.A mixture of (R)-tert-butyl1-(5,6-dichloropyridazin-4-yl)pyrrolidin-3-yl(methyl) carbamate (400 mg,1.15mmol) and 2-phenylethanamine (1mL) was stirred at 150° C. for 40 minin microwave. The mixture was concentrated and the residue was purifiedby silica gel chromatography (MeOH/DCM= 1/50, v/v) to afford the desiredproduct (295 mg, 59%). LC-MS: m/z=432.1[M+H]⁺.

(R)-tert-butylmethyl(1-(6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl) carbamate. To a mixture of(R)-tert-butyl1-(5-chloro-6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl(methyl)-carbamate (295 mg, 0.68 mmol) and HCOONH₄ (0.5 g, 7.9 mmol) in MeOH (15mL) was added 10% Pd/C (0.3 g) and the resulting mixture was refluxed 30min. The reaction was allowed to cool and filtered. The filtrate wasconcentrated, then diluted with EA (20 mL) and washed with brine (10mL*2). The combined organic layer was dried over Na₂SO₄, filtered,concentrated and purified by prep-HPLC to give the product as oil (177mg, 65%). ¹H NMR (300 MHz, CDCl₃): δ 8.80 (s, 1 H), 7.70 (d, J=5.4 Hz1H), 7.30-7.18 (m, 5H), 5.30 (5.30, J=9.6 Hz, 1H), 4.86 (d, J=6.3Hz,1H), 3.78-3.73 (m, 1H), 3.49-3.35 (m, 4H), 2.96 (t, J=7.2 Hz, 2H), 2.82(s, 3H), 2.23 (s,2H), 1.48 (s, 9H); LC-MS: m/z=398.1 [M+H]⁺.

(R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-phenethylpyridazin-3-aminedihydrochloride. To a solution of(R)-tert-butylmethyl(1-(6-(phenethylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate (177 mg, 44 mmol) in MeOH (3 mL) was addedether solution of HCl gas (7N, 10 mL). The reaction was stirred at roomtemperature for 16 hours. The solution was concentrated under reducedpressure to give the desired product as a white solid (32.2 mg, 20%).¹HNMR (300 MHz, CD₃OD): 8.13 (d, J =2.4 Hz, 1H), 7.33-7.25 (m, 5H), 5.98(d, J=2.4 Hz, 1H), 4.01-3.62 (m, 7H), 3.00 (t, J=6.9 Hz, 2H), 2.84 (s,3H), 2.60-2.30 (m, 2H); LC-MS: m/z=298.3[M+H]⁺, t_(R)=1.0 min; HPLC: 98%(214 nm), 99% (254 nm), t_(R)=7.1 min.

The compounds in Example 373 through Example 403 were prepared usingmethods analogous to those described in Example 372.

Example 373N-[(1R)-1-Cyclohexylethyl]-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₉N₅, 303.45 m/z found, 304.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.11 (s, 1H), 6.04 (s, 1H), 4.05-3.56 (m, 6H),2.82 (s, 3H), 2.59-2.54 (m, 1H), 2.40-2.30 (m, 1H), 1.90-1.70 (m, 5H),1.60-1.00 (m, 9H).

Example 374N-(Bicyclo[2.2.1]hept-2-ylmethyl)-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₇N₅, 301.44 m/z found, 302.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.18 (d, J=2.1 Hz, 1H), 6.13 (d, J=2.1 Hz, 1H),4.20-3.50 (m, 5H), 3.40-3.10 (m, 2H), 2.88 (s, 3H), 2.67-2.62 (m, 1H),2.50-2.20 (m, 3H), 2.00-0.82 (m, 9H).

Example 375N-(Bicyclo[2.2.1]hept-2-ylmethyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₇N₅, 301.44 m/z found, 302.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.4 Hz, 1H), 6.13 (d, J=2.4 Hz, 1H),4.20-3.50 (m, 5H), 3.40-3.10 (m, 2H), 2.88 (s, 3H), 2.65-2.60 (m, 1H),2.50-2.20 (m, 3H), 2.00-0.82 (m, 9H).

Example 376N-(2-Methoxyethyl)-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.18 (s, 1H), 6.14 (s, 1H), 4.10-3.57 (m, 9H),3.44 (s, 3H), 2.87 (s, 3H), 2.70-2.30 (m, 2H).

Example 377N-Cyclopropyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (s, 1H), 6.01 (s, 1H), 4.01-3.73 (m, 5H),2.78 (s, 3H), 2.57-2.50 (m, 2H), 2.31-2.29 (m, 1H), 0.94-0.92 (m, 2H),0.64 (s, 2H).

Example 378N-[(1R)-1-Cyclohexylethyl]-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₉N₅, 303.45 m/z found, 304.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (s, 1H), 6.05 (s, 1H), 4.10-3.50 (m, 6H),2.82 (s, 3H), 2.70-2.50 (m, 1H), 2.40-2.30 (m, 1H),1.88-1.69 (m, 5H),1.60-1.03 (m, 9H).

Example 3795-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.36 m/z found, 250.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.14 (s, 1H), 6.05 (s, 1H), 4.05-3.60 (m, 5H),3.15 (d, J=6.9 Hz, 2H), 2.83 (s, 3H), 2.59-2.55 (m, 1H), 2.35-2.30 (m,1H), 1.98-1.93 (m, 1H), 1.03 (d, J=6.6 Hz, 6H).

Example 380N-Cyclopentyl-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (s, 1H), 6.06 (s, 1H), 4.06-3.60 (m, 6H),2.86 (s, 3H), 2.60 (m, 1H), 2.41(m, 1H), 2.14-1.33 (m, 8H).

Example 381N-Bicyclo[2.2.1]hept-2-yl-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.18 (d, J=2.4 Hz, 1H), 6.04 (d, J=2.1 Hz, 1H),4.11-3.39 (m, 6H), 2.87 (s, 3H), 2.66-2.59 (m, 1H), 2.42-2.35 (m, 3H),2.02-1.95 (m, 1H), 1.70-1.24 (m, 7H).

Example 382N-(Cyclopentylmethyl)-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-aminef

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.02 (d, J=1.8Hz, 1H), 5.97 (s, 1H), 3.96-3.44 (m,5H), 3.25 (s, 2H), 3.15 (d, J=7.2Hz, 2H), 2.67 (s, 3H), 2.51-2.44 (m,1H), 2.30-2.26 (m, 1H), 2.15-2.08 (m, 1H), 1.84-1.78 (m, 2H), 1.60-1.52(m, 4H), 1.24-1.18 (m, 2H).

Example 3832,2-Dimethyl-3-({5-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.39 m/z found, 266.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (s, 1H), 6.21 (s, 1H), 4.09-3.58 (m, 5H),3.39 (s, 2H), 3.28 (s, 2H), 2.81 (s, 3H), 2.62--2.58 (m, 1H), 2.39-2.37(m, 1H), 1.03 (s, 6H).

Example 3845-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(4-methylbenzyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (s, 1 H), 7.30 (d, J=7.2 Hz, 2H), 7.22 (d,J=7.2 Hz, 2H), 6.06 (s, 1H), 4.53 (s, 2H), 4.15-3.50 (m, 5H), 2.83 (s,3H), 2.61-2.55 (m, 1H), 2.40-2.30 (m, 1H), 2.35 (s, 3H).

Example 385N-(2,2-Dimethylpropyl)-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.39 m/z found, 264.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (d, J=1.8Hz, 1H), 6.15 (s, 1H), 4.08-3.81 (m,5H), 3.15 (s, 2H), 2.81 (s, 3H), 2.59-2.57 (m, 1H), 2.39-2.36 (m, 1H),1.03 (s, 9H).

Example 3865-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(4,4,4-trifluorobutyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₀F₃N₅, 303.33 m/z found, 304.1 [M+H]⁺.CD₃OD: 8.06 (s, 1H), 6.00 (s, 1H), 4.10-3.50 (m, 5H), 3.34 (t, J=6.6 Hz,2H), 2.73 (s, 3H), 2.60-2.40 (m, 1H), 2.40-2.20 (m, 3H), 1.90-1.80 (m,2H).

Example 387N-(Furan-3-ylmethyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₁₉N₅O, 273.34 m/z found, 274.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 6.49 (s,1H), 6.08 (s, 1H), 4.42 (s, 2H), 4.10-3.40 (m, 5H), 2.81 (s, 3H),2.70-2.50 (m, 1H), 2.40-2.20 (m, 1H).

Example 388N-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (d, J=2.1 Hz, 1H), 6.06 (s, 1H), 4.08-3.80(m, 5H), 2.79 (s, 3H), 2.63-2.56 (m, 1 H), 2.47-2.35 (m, 4H), 2.08-1.98(m, 7H, contain paraffin), 1.61-1.56 (m, 1H), 1.27 (s, 3H), 1.12 (s,3H), 1.06-1.00 (m, 1H).

Example 3895-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(4,4,4-trifluorobutyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₃H₂₀F₃N₅, 303.33 m/z found, 304.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.18 (d, J=1.8 Hz, 1H), 6.08 (s, 1H), 4.08-3.56(m, 5H), 3.45 (t, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.64-2.57 (m, 1H),2.40-2.31 (m, 3H), 2.00-1.90 (m, 2H).

Example 3903-({5-[(3R)-3-(Methylamino)pyrrolidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.08 (s, 1H), 6.02 (s, 1H), 4.01-3.63 (m, 7H),3.42 (t, J=6.6 Hz, 2H), 2.78 (s, 3H), 2.57-2.50 (m, 1 H), 2.30 (br, s,1H), 1.88-1.80 (m, 2H).

Example 391N-(Cyclohexylmethyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₇N₅, 289.43 m/z found, 290.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (s, 1H), 6.05 (s, 1H), 4.10-3.40 (m, 5H),3.16 (d, J=6.9 Hz, 2H), 2.82 (s, 3H), 2.70-2.50 (m, 1H), 2.40-2.30 (m,1H),1.90-1.60 (m, 6H), 1.40-1.00 (m, 5H).

Example 392N-(2,2-Dimethylpropyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₅N₅, 263.39 m/z found, 264.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.14 (s, 1H), 6.18 (s, 1H), 4.07-3.50 (m, 5H),3.17 (s, 2H), 2.83 (s, 3H), 2.58 (m, 1H), 2.38 (m, 1H), 1.04 (s, 9H).

Example 393N-(2-Methoxyethyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.13 (s, 1H), 6.11 (s, 1H), 4.06-3.54 (m, 9H),3.39 (s, 3H), 2.82 (s, 3H), 2.58 (m, 1H), 2.40 (m, 1H).

Example 394N-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₉H₃₁N₅, 329.49 m/z found, 330.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (s, 1H), 6.06 (s, 1H), 4.08-3.58 (m, 5H),2.84 (s, 3H), 2.63-2.37 (m, 4H), 2.16-1.98 (m, 6H), 1.66-1.59 (m, 1H),1.37-1.32 (m, 1H), 1.27 (s, 3H), 1.12 (s, 3H), 1.06-1.00 (m, 1H).

Example 395N-Cyclopropyl-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.32 m/z found, 234.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.17 (d, J=2.7 Hz, 1H), 6.05 (d, J=1.8 Hz, 1H),4.07-3.60 (m, 5H), 2.82 (s, 3H), 2.66-2.54 (m, 2H), 2.39-2.34 (m, 1H),1.00-0.94 (m, 2H), 0.70-0.65 (m, 2H).

Example 396N-(Cyclohexylmethyl)-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₇N₅, 289.43 m/z found, 290.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (s, 1H), 6.05 (s, 1H), 4.10-3.40 (m, 5H),3.16 (d, J=6.9 Hz, 2H), 2.82 (s, 3H), 2.70-2.50 (m, 1H), 2.40-2.30 (m,1H),1.90-1.60 (m, 6H), 1.40-1.00 (m, 5H).

Example 397N-Benzyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.38 m/z found, 284.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.19 (d, J=2.1 Hz, 1H), 7.45-7.37 (m, 5H), 6.12(s, 1H), 4.62 (s, 2H), 4.09-3.52 (m, 5H), 2.86 (s, 3H), 2.62-2.58 (m,1H), 2.44-2.40 (m, 1H).

Example 398N-(4-Fluorobenzyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₀FN₅, 301.37 m/z found, 302.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.05 (s, 1H), 7.36-7.32 (m, 2H), 7.05-7.00 (m,2H), 5.96 (s, 1H), 4.46 (s, 2H), 3.95-3.40 (m, 5H), 2.71 (s, 3H),2.48-2.43 (m, 1H), 2.40-2.20 (m, 1H).

Example 399N-(4-Fluorobenzyl)-5-[(35)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₀FN₅, 301.37 m/z found, 302.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.17 (s, 1H), 7.46-7.42 (m, 2H), 7.18-7.12 (m,2H), 6.06 (s, 1H), 4.56 (s, 2H), 4.15-3.47 (m, 5H), 2.82 (s, 3H),2.62-2.55 (m, 1H), 2.42-2.34 (m, 1H).

Example 400N-(4-Methoxybenzyl)-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅O, 313.41 m/z found, 314.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.16 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H),6.96 (d, J=8.7 Hz, 2H), 6.06 (s, 1H), 4.50 (s, 2H), 4.13-3.56 (m, 5H),3.83 (s, 3H), 2.83 (s, 3H), 2.62-2.55 (m, 1H), 2.39-2.35 (m, 1H).

Example 4015-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R)-1-phenylethyl]pyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.1 [M+H]⁺.CD₃OD: 8.12 (d, J=2.4 Hz, 1H), 7.49-7.31 (m, 5H), 6.01 (s, 1 H),4.04-3.36 (m, 6H), 2.82 (s, 3H), 2.58-2.53 (m, 1H), 2.37-2.33 (m, 1 H),1.63 (d, J=6.6 Hz, 3H).

Example 4025-[(35)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.37 m/z found, 285.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.79 (d, J=5.1 Hz, 1H), 8.39 (t, J=7.8 Hz, 1H),8.25 (d, J=2.1Hz, 1H), 7.94-7.82 (m, 2H), 6.27 (br, s, 1H), 5.01 (s,2H), 4.07-3.60 (m, 7H), 2.84 (s, 3H), 2.61-2.56 (m, 1H), 2.38-2.36 (m,1H).

Example 4033-({5-[(35)-3-(Methylamino)pyrrolidin-1-yl]pyridazin-3-yl}amino)propan-1-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₆O, 251.33 m/z found, 252.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.12 (d, J=2.1 Hz, 1H), 6.05 (d, J=2.1 Hz, 1H),4.07-3.67 (m, 7H), 3.44 (t, J=6.9 Hz, 2H), 2.77 (s, 3H), 2.61-2.54 (m,1H), 2.38-2.31 (m, 1H), 1.92-1.84 (m, 2H).

Example 404N-(2,2-DimethylpropyI)-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

5-iodopyridazin-3(2H)-one. A mixture of 4,5-dichloropyridazin-3(2H)-one(25 g, 0.152 mol) in 250 mL of hydrogen iodide acid (57 w %) was heatedto reflux for 18 hrs. The solution was cooled to ambient temperature andfiltered. The precipitate was washed with saturated sodium thiosulfatesolution. The precipitate was dried to give the desired product as ayellow solid (Int. Pat. Appl. Publ. WO 2008/013838 (Cephalon Inc., Jan.31, 2008)) (15 g, 45%). ¹H NMR (300 MHz, CDCl₃): 13.26 (br s, 1H), 8.08(s, 1H), 7.54(s, 1H); LC-MS: m/z=222.9 [M+H]⁺.

5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one. A solution of5-iodopyridazin-3(2 H)-one (0.1 g, 0.45 mmol) and 1-methylpiperazine(0.09 g, 0.9 mmol) in ethanol (10 mL) was heated to reflux for 18 hrs.The solvent was removed under reduce pressure to give a crude oil. Thecrude oil was purified by silica gel chromatography (DCM/MeOH=30/1, v/v)to give yellow solid (60 mg, 68%). ¹H NMR (300 MHz, DMSO-d₆): 12.20 (brs, 1H), 7.92 (s, 1H), 5.72(s, 1H), 3.33-3.29(m, 4H), 2.38-2.35 (s, 4H),2.19 (s, 3H); LC-MS: m/z=195.0 [M+H]⁺.

3-chloro-5-(4-methylpiperazin-1-yl)pyridazine. A solution of5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one (5.82 g, 0.03 mol) in 25mL of phosphoryl trichloride was heated to 80° C. for 3 hrs. Thesolution was concentrated and diluted with NaOH solution (0.5N) and pHwas adjusted to 10. The solution was extracted with DCM (3×150 mL),washed with brine (3×100 mL), dried over Na₂SO₄, concentrated to givethe crude oil. The residue was purified by silica gel chromatography(DCM/MeOH=40/1, v/v) to give colorless solid (1.4 g, 22%). ¹H NMR (300MHz, CDCl₃): 8.75 (s, 1H), 6.68 (s, 1H), 3.47-3.44 (m, 4H), 2.57 (s,4H), 2.38 (s, 3H); LC-MS: m/z=213.1 [M+H]⁺

5-(4-methylpiperazin-1-yl)-N-neopentylpyridazin-3-amine diformic acid. Asolution of 3-chloro-5-(4-methylpiperazin-1-yl)pyridazine (212 mg, 1mmol) in 1 mL of 2,2-dimethylpropan-1-amine was stirred at 200° C. inmicrowave for 20 min. The solution was concentrated and purified bysilica gel chromatography to give the crude solid which was furtherpurified by prep-HPLC to give the title product (160 mg, 43%). ¹H NMR(300 MHz, CDCl₃): 14.44 (s, 1H), 9.34 (s, 1H), 8.40 (s, 2H), 7.91(s,1H), 5.90 (s, 1H), 3.50 (s, 4H), 2.90 (s, 2H), 2.57 (s, 4H), 2.29 (s,3H), 0.88 (s, 9H); LC-MS: m/z=264.1 [M+H]⁺.

5-(4-methylpiperazin-1-yl)-N-neopentylpyridazin-3-amine dihydrochloride. A solution of hydrogen chloride in ether (7N, 20 mL) was addedinto a solution of5-(4-methylpiperazin-1-yl)-N-neopentylpyridazin-3-amine diformic acid inMeOH (3mL). The mixture was stirred at ambient temperature for 18 hrs.The solvent was removed by reduce pressure to give the title product(160 mg, 100%). ¹H NMR (300 MHz, CD₃OD): 8.41(s, 1H), 6.58 (s, 1H),4.40-4.35 (m, 2H), 4.00-3.40 (m, 6H), 3.22 (s, 2H), 3.02 (s, 3H), 1.08(s, 9H); LC-MS: m/z=264.1 [M+H]⁺. MS (ESI): mass calcd. for C₁₄H₂₅N₅,263.39 m/z found, 264.1 [M+H]⁺.

The compounds Example 405 through Example 411 were prepared usingmethods analogous to those described in Example 404.

Example 405N-(2-Methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.33 m/z found, 252.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.38 (s, 1 H), 6.46 (s, 1H), 4.35 (br s, 2H),3.90-3.20 (m, 10H), 3.40 (s, 3H), 2.99 (s, 3H)

Example 406N-Bicyclo[2.2.1]hept-2-yl-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.41 m/z found, 288.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.37 (d, J=2.4 Hz, 1H), 6.34 (d, J=2.7 Hz, 1H),4.28 (br, s, 2H), 3.63-3.51 (m, 6H), 2.98 (m, 3H), 2.37-1.97 (m, 2H),1.97-1.90 (m, 1H), 1.62-1.19 (m, 8H).

Example 407 N-Cyclopentyl-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.1 [M+H]⁺. ¹H5NMR (300 MHz, CD₃OD): 8.41 (s, 1H), 6.41 (s, 1H), 4.33-3.57 (m, 9H),3.02 (s, 3H), 2.13 (br s, 2H), 1.83-1.69 (m, 6H).

Example 408N-(Cyclopentylmethyl)-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.4 m/z found, 276.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.35 (d, J=3.0 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H),4.91-3.23 (m, 10H), 2.97(s, 3H), 2.27-2.17 (m, 1H), 1.90-1.82 (m, 2H),1.72-1.59 (m, 4H), 1.58-1.26 (m, 2H).

Example 409 5-(4-Methylpiperazin-1-yl)-N-(2-phenylethyppyridazin-3-amine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.41 m/z found, 298.2 [M+H]⁺. ¹HNMR (300 MHz, D₂O): 8.04 (s, 1H), 7.27-7.18 (m, 5H), 5.89 (s, 1H), 4.02(br s, 2H), 3.58-3.54 (m, 4H), 3.32 (br s, 2H), 3.11 (br s, 2H), 2.87(s, 3H), 2.85 (m, 2H).

Example 410 N-Benzyl-5-(4-methylpiperazin-1-yl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₆H₂₁ N₅, 283.38 m/z found, 284.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.41 (d, J=1.2Hz, 1H), 7.41-7.31 (m, 5H), 6.48 (s,1H), 4.60 (s, 2H), 4.35 (br s, 4H), 3.60 (br s, 4H), 2.98 (s, 3H).

Example 4115-(4-Methylpiperazin-1-yl)-N-(pyridin-2-ylmethyl)pyridazin-3-amine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.37 m/z found, 285.3 ¹H NMR (300MHz, CD₃OD): 8.77 (d, J=5.4 Hz, 1H), 8.47-8.42 (m, 2H), 7.97-7.85 (m,2H), 6.63 (s, 1H), 5.03 (s, 2H), 4.38 (br, 2H), 3.59-3.26 (m, 6H), 2.94(s, 3H), (trace of ether).

Example 412:N-cyclopentyl-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridazin-3-amine

The titled compound was prepared in a manner analogous to Example 101.MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.37 m/z found, 262.2 [M+H]⁺. ¹HNMR (400 MHz, D₂O) d 8.01 (d, J=2.5, 1H), 5.90 (d, J=2.4, 1H), 4.12-4.05(m, 1H), 4.03-3.92 (m, 2H), 3.91-3.57 (m, 3H), 2.80 (s, 3H), 2.64-2.50(m, 1H), 2.38-2.29 (m, J=5.7, 1H), 2.09-1.95 (m, J=6.6, 2H), 1.79-1.54(m, 7H).

Example 413(R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(1-adamantyl)pyridazin-3-aminedihydrochloride

(R)-tert-butyl 1-(6-chloropyridazin-4-yl)pyrrolidin-3-ylcarbamate. Asolution of 3,5-dichloropyridazine (4.47g, 30mmol), (R)-tert-butylpyrrolidin-3-ylcarbamate (5.59g, 30mmol) and triethylamine (8.1g,80mmol) in THF (50 mL) was stirred at ambient temperature for 20 hrs.The solvent was removed under reduced pressure and the residue waspurified by column chromatography to afford the desired product (5.4 g,60%) as a colorless solid. LC-MS: m/z=299.2 [M+H⁺]⁺.

(R)-tert-butyl-1-(6-chloropyridazin-4-yl)pyrrolidin-3-yl(methyl)carbamate. A solution of (R)-tert-butyl1-(6-chloropyridazin-4-yl)pyrrolidin-3-ylcarbamate (3.6 g, 12.05 mmol)in N,N-dimethylformamide (DMF, 40 mL) was added into a suspension of 60%sodium hydride (0.58 g, 14.5 mmol) in DMF (40 mL) at 0° C. The mixturewas stirred at 0° C. for further 30 min then lodomethane (2.06 g, 14.5mmol) was added into the mixture and the resulting reaction was stirredfor further 3 h at ambient temperature. Water (100 mL) was added and themixture was extracted with dichloromethane. The combined organic layerwas dried over Na₂SO₄, filtered and concentrated. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography to afford the desired product (2.5 g, 66%) as a brownsolid. ¹H NMR (300 MHz, CDCl₃): 8.47 (d, J=2.4 Hz, 1H), 6.41 (d, J=2.4Hz, 1 H), 4.89 (br s, 1H), 3.58-3.52 (m, 2H), 3.42-3.36 (m, 1H),3.29-3.23 (m, 1H), 2.82 (s, 3H), 2.27-2.14 (m, 2H), 1.47 (s, 9H).

(R)-tert-butylmethyl(1-(6-(1-adamantylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate.A mixture of (R)-tert-butyl1-(6-chloropyridazin-4-yl)pyrrolidin-3-yl(methyl) carbamate (78 mg, 0.25mmol), 1-adamantylamine (76 mg, 0.5 mmol), BINAP (10.9 mg, 0.0175 mmol),palladium acetate(3.9 mg, 0.0175 mmol) and t-BuONa (72.1 mg, 0.75 mmol)in 1,2-dimethoxyethane(2 mL) was charged with N₂. The reaction mixturewas stirred at 80° C. for 1.5 hours. The solution was diluted with ethylacetate (5 mL) and washed with 5% NaHCO₃ solution. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography 0-3.5% NH₃ MeOH/DCM to afford the desired product (64 mg,60%) as a colorless solid. LC-MS: m/z=428.3 [M+H]⁺.

(R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(1-adamantyl)pyridazin-3-aminedihydrochloride. (R)-tert-butylmethyl(1-(6-(1-adamantylamino)pyridazin-4-yl)pyrrolidin-3-yl)carbamate(120 mg, 0.28 mmol) was dissolved in MeOH (4 mL) and 7N HCl/Et₂Osolution (20 mL) was added. The resulting solution was stirred atambient temperature for 18 hrs. The solvent was concentrated to give thedesired product as a light yellow solid (73 mg, 60%). MS (ESI): masscalcd. for C₁₉H₂₉N₅, 327.48 m/z found, 328.3 [M-F1-1]⁺. ¹H NMR (300 MHz,CD₃OD): 8.15 (s, 1H), 6.12 (s, 1H), 4.08-3.60 (m, 5H), 2.84 (s, 3H),2.61-2.56 (m, 1H), 2.42-2.38 (m, 1H), 2.20 (s, 3H), 2.10 (s, 6H),1.87-1.77 (m, 6H).

The compounds in Examples 414 through 416 were made analogously toExample 413.

Example 414(R)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(2-adamantyl)pyridazin-3-aminedihydrochloride

MS (ESI): mass calcd. for C₁₉H₂₉N₅, 327.48 m/z found, 328.3 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (d, J=2.4 Hz, 1H), 6.26 (s, 1H), 4.08-3.60(m, 6H), 2.84 (s, 3H), 2.60-2.56 (m, 1H), 2.42-2.37 (m, 1H), 2.11-1.85(m, 12H), 1.76-1.71 (m, 2H).

Example 415(S)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(2-adamantyl)pyridazin-3-aminedihydrochloride

MS (ESI): mass calcd. for C₁₉H₂₉N₅, 327.48 m/z found, 328.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (d, J=2.1 Hz, 1H), 6.26 (s, 1H), 4.91-3.61(m, 6H), 2.84 (s, 3H), 2.63-2.56 (m, 1H), 2.42-2.37 (m, 1H), 2.11-1.85(m, 12H), 1.75-1.71 (m, 2H).

Example 416(S)-5-(3-(methylamino)pyrrolidin-1-yl)-N-(1-adamantyl)pyridazin-3-aminedihydrochloride

MS (ESI): mass calcd. for C₁₉H₂₉N₅, 327.48 m/z found, 328.2 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD): 8.15 (s, 1H), 6.12 (s, 1H), 4.08-3.60 (m, 5H),2.84 (s, 3H), 2.61-2.56 (m, 1H), 2.42-2.38 (m, 1H), 2.38 (s, 3H), 2.10(s, 6H), 1.87-1.77 (m, 6H).

Binding Assay on Recombinant Human Histamine H₄ Receptor.

Cell pellets from SK-N-MC cells stably or transiently transfected withhuman H₄ receptor (NCBI accession No. AF312230) were used for thebinding assays. Cell pellets were homogenized in 50 mM Tris/5 mM EDTAbuffer and supernatants from an 800g spin were collected andrecentrifuged at 30,000g for 30 min. Pellets were rehomogenized in 50 mMTris/5 mM EDTA buffer. For competition binding studies, cell membraneswere incubated with 2× K_(D) (10 nM), [³H] histamine (Specific activity:14.2 to 23 C_(i)/mmol), with or without test compounds for 45 to 60 minat 4 to 25° C. K_(i) values were calculated based on an experimentallydetermined appropriate K_(D) values according to Cheng and Prusoff(Biochem. Pharmacol. 1973, 22(23): 3099-3108). Membranes were harvestedby rapid filtration using the 96 well Brandel system (Table 1, Brandel)or a cell harvester (Table 1, Cell Harvester) using a Whatman GF/Cfilter or filter plates treated with 0.5% polyethylenimine (PEI), andwashed 4 times with ice-cold 50 mM Tris/5 mM EDTA buffer. Filters werethen dried, mixed with scintillant and radioactive counts weredetermined. Results for the compounds tested in these assays arepresented in Table 1 as an average of results obtained (NT=not tested,ND=not determined). Compounds were tested in free base, hydrochloridesalt, or trifluoroacetic acid form, with no significant differences inactivities. Where activity is shown as greater than (>) a particularvalue, the value is the highest concentration tested.

TABLE 1 Cell Example Harvester Brandel # K_(i) (nM) K_(i) (nM)  1 0.5 1 2 3.83  3 7.26  4 4.9  5 8.9  6 35.1  7 13.7  8 10.6  9 0.4 1  10 0.50.5  11 12.9  12 19.2  13 26.2  14 114.39  15 148.9 54.3  16 48.19  17375.49  18 527.35  19 NT 45.3  20 NT 3.5  21 NT 51.4  22 1.5 1.7  23 2.7 24 3.32  25 3.8  26 5.5  27 67.7  28 8.4  29 58.51  30 91.79 42.4  3176.9 69.02  32 1.69 3.08  33 0.9  34 18.1  35 74.7 25.6  36 103.8 91.31 37 247.12  38 275.42  39 554.24  40 790.32  41 2.2  42 31.8  43 3.3  4485.7 31.5  45 7.1  46 8.4  47 33.2  48 26.7  49 27.6  50 33.2  51 123.11 52 33.4  53 85.7 24.3  54 87.9  55 101.79 137.5  56 567.81  57 139.7 58 341.9  59 190.11  60 341.9  61 >10,000  62 >10,000  63 292.69  6465.19 39  65 68.6 46.3  66 56.79 12.2  67 275.42  68 36.7  69 >10,000 70 73 240.27  71 377.14  72 376.27  73 0.7 2  74 1.2  75 1.5  76 1.8 77 3.3  78 6  79 11.6  80 23.5  81 24.7  82 45.5  83 195.79  84 33.3 85 18.2  86 33.7  87 33.7  88 42.7  89 69.29 26.2  90 105.61 68.9  91182.18  92 615.32  93 701.62  94 868.36  95 15 15  96 1 1  97 5.9 5.9 98 4.8 4.8  99 23.9 23.9 100 31 31 101 >10,000 >10,000 102 45.93 103167.9 104 1053 105 165 106 193.9 107 69.91 108 140.6 109 63.96 110 837.2111 93.55 112 236.1 113 139.5 114 45.39 115 931.7 116 7.532 117 246.5118 >10,000 119 22.87 120 302.7 121 1.569 122 64.71 123 2.038 124 155.4125 2.096 126 19.84 127 1.659 128 843.9 129 141.4 130 849.2 131 820.4132 1544 133 128.9 134 696.8 135 15.91 136 193.2 137 1378 138 23.82 1397.958 140 135.3 141 2322 142 7094 143 266.8 144 2533 145 923 146 34.09147 6.662 148 249.8 149 23.84 150 29.71 151 1459 152 2297 153 43.57 154203.6 155 744.5 156 413.3 157 2144 158 3485 159 265.9 160 86.7 161 1301162 7.137 163 277.7 164 36.2 165 731.9 166 >10,000 167 34.91 168 483.1169 9.672 170 143.8 171 3.893 172 13.74 173 745.2 174 19.09 175 816.3176 457.7 177 522.9 178 242.8 179 788.2 180 116.4 181 9.066 182 45.41183 15.64 184 1.576 185 1732 186 690.6 187 71.55 188 449.7 189 5.729 1901.678 191 3.575 192 2.419 193 15.97 194 5.07 195 7.75 196 224.5 19717.34 198 54.99 199 2300 200 859.9 201 62.29 202 194.5 203 61.38 204 NT205 no data 206 44.85 207 191.1 208 0.86 209 1458 210 295.8 211 1.684212 274.6 213 156.7 214 415.9 215 69.65 216 1434 217 24.27 218 2.615 219187.7 220 6.48 221 853.2 222 67.29 223 722.6 224 238.7 225 75.06 2263.813 227 259.5 228 31.76 229 >10,000 230 275.9 231 8.412 232 716 233215 234 7259 235 409.3 236 47.35 237 584.5 238 555.4 239 700.8 240 54.34241 837.5 242 >10,000 243 167 244 3883 245 227.7 246 395.4 247 1.41 248NT 249 257.4 250 658.9 251 79.38 252 190.4 253 4.33 254 27.54 255 1944256 616.8 257 64.49 258 >10,000 259 5.148 260 >10,000 261 3563 262 22.07263 3091 264 >10,000 265 1.71 266 14.47 267 1529 268 246.5 269 2099 2703.526 271 189.3 272 2102 273 3166 274 10.57 275 8.548 276 1638 277 97.04278 7.29 279 275.6 280 9.955 281 21.26 282 173.2 283 162.4 284 42.33 285140.9 286 88.28 287 98.92 288 39.47 289 409.7 290 1479 291 238.9 2927.01 293 60.94 294 103.3 295 162.9 296 64.23 297 1556 298 >10,000 299146.2 300 1857 301 202.1 302 98.12 303 416.8 304 310.4 305 1059 306 7216307 535.7 308 18.43 309 1597 310 620.8 311 226.3 312 546.8 313 >10,000314 >10,000 315 1919 316 275.4 317 929.8 318 1237 319 478.3 320 4314 321626.2 322 88.05 323 >10,000 324 898.7 325 797.8 326 2743 327 95.32 3281677 329 >10,000 330 2586 331 96.73 332 1658 333 >10,000 334 2574335 >10,000 336 >10,000 337 >10,000 338 >10,000 339 219.7 340 2033341 >10,000 342 936.4 343 >10,000 344 >10,000 345 1316 346 >10,000347 >10,000 348 >10,000 349 >10,000 350 1723 351 205.8 352 >10,000 353105.6 354 2131 355 2900 356 1597 357 4370 358 >10,000 359 161.3 360 1171361 1227 362 2212 363 4727 364 1743 365 508.1 366 >10,000 367 866.9 368290.4 369 619.4 370 223.6 371 130.3 372 138.6 373 143.1 374 297.8 37566.75 376 >10,000 377 698.9 378 6.164 379 296 380 54.29 381 5.51 382138.5 383 596 384 2004 385 258.8 386 283.9 387 835.1 388 293.4 389 1745390 >10,000 391 36.47 392 18.35 393 1807 394 633.6 395 1902 396 380.5397 353.4 398 347.4 399 3941 400 2152 401 79.31 402 >10,000 403 >10,000404 4303 405 >10,000 406 178.1 407 823.6 408 >10,000 409 >10,000410 >10,000 411 NT 412 5.6 413 NT 414 NT 415 NT 416 NTCell-Based cAMP Assay

SK-N-MC cell lines were created that express a reporter gene constructand the human H4 receptor full-coding region (NCBI accession No.AF312230). The reporter gene was R-galactosidase under the control ofcyclic AMP-responsive elements. Cells were plated in 96-well plates thenight before the assay. Histamine was used as the agonist for all assay.For the H4 receptor, the inhibition of forskolin-stimulated cAMPproduction was measured. For determination of antagonist activity,compounds were added 10 min prior to the addition of agonist, which wasadded directly to the cell medium. Forskolin (5 μM final concentration)was added 10 min after the addition of histamine. Cells were returned tothe incubator for 6 h at 37° C. The medium was then aspirated, and thecells were washed with 200 mL of phosphate-buffered saline (PBS). Cellswere lysed with 25 μL of 0.1× assay buffer (10 mM sodium phosphate, pH8, 0.2 mM MgSO₄, and 0.01 mM MnCl₂) and incubated at rt for 10 min.Cells were then incubated for 10 min with 100 μL of 1× assay buffercontaining 0.5% (v/v) Triton X-100 and 40 mM β-mercaptoethanol. Colorwas developed using 25 μL of 1 mg/mL substrate solution (chlorophenolred β-D-galactopyranoside; Roche Applied Science, Indianapolis, Ind.).Color was quantitated on a microplate reader by measuring the absorbanceat 570 nm. The data from each concentration-response curve were fittedto a sigmoidal curve to obtain the maximum response, Hill coefficient,and EC₅₀ using Prism (GraphPad Software, San Diego, Calif.). Dose ratioswere calculated from individual concentration-response curves ofagonists at three to five antagonist concentrations. Apparent pA₂ valueswere calculated using a Schild plot (ND=not determined). Results forcompounds tested in this assay are presented in Table 2.

Example # pA₂  2 ND  3 8.7  4 8.86  12 8.5  20 7.7  22 9.24  32 11  33ND  95 7.8 162 8.1 189 8 193 7.9 201 7.7 203 7.8 217 7.5 220 7.6 228 7.4231 9 257 7.3 308 7.1 331 7.4 380 7.2 381 8.1 392 8.1

While the invention has been illustrated by reference to examples, it isunderstood that the invention is intended not to be limited to theforegoing detailed description.

Insulin Resistance in Diabetes Induced Obese Mouse Model.

The effect of administration of an H4R antagonist,5-fluoro-4-methyl-2-{5-methyl-244-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole(U.S. Pat. No. 7,432,378, Example 165), was tested in the treatment ofinsulin resistance in the diabetes induced obese (DIO) mouse model.5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole(20 mg/kg PO) significantly reduced fed and fasted glucose levels andimproved insulin sensitivity as determined by an insulin tolerance test.5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazolesignificantly reduced fat content in liver and reduced MCP-1 and TNF-αexpression. Our data support the claim that H4R antagonists havebeneficial properties towards the treatment of type 2 diabetes andrelated metabolic diseases.

What is claimed is:
 1. A chemical entity selected from the compounds ofFormula (I)

wherein Z is CH; Y is CH; R¹ is: a) —(CH₂)₂OCH₃, —(CH₂)₂SCH_(3,) or C₁₋₈alkyl, each independently unsubstituted or substituted with —OH or —CF₃;b) —(CH₂)₀₋₂—Ar¹, —CHR²—Ar¹, or —(CH₂)₀₋₂—Ar², each of said Ar¹ and Ar²independently unsubstituted or substituted with halo, —CH_(3,) or—OCH_(3,) Ar¹ is a 6-membered aromatic carbocyclic ring, Ar² is a 5 to6-membered heteroaromatic ring containing N, S or O; or c) cycloalkyl,—(CH₂)-(monocyclic cycloalkyl), —(CH₂)-(bridged polycyclic cycloalkyl),—(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH₂)-(bridged monocyclic cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl, each of said cycloalkyl independentlyunsubstituted or substituted with one, two, or three C₁₋₄ alkylsubstituents; R² is —C₁₋₄ alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃ alkyl;provided that: when R¹ is isopropyl, then R^(c) is methyl; when R¹ is4-methylphenyl, then R^(c) is methyl; and pharmaceutically acceptablesalts of compounds of Formula (1). 2-5. (canceled)
 6. A chemical entityof claim 1, wherein R¹ is selected from the group consisting of:

and


7. A chemical entity of claim 1, wherein

is selected from the group consisting of:


8. A chemical entity of claim 1, wherein

is


9. A chemical entity of claim 1, wherein

is


10. A chemical entity of claim 1, wherein

is


11. A chemical entity of claim 1, wherein

is


12. A chemical entity of claim 1, wherein

is


13. A chemical entity of claim 1, wherein R^(a) is H.
 14. A chemicalentity of claim 1, wherein R^(b) is H or methyl.
 15. A chemical entityof claim 1, wherein R^(c) is H or methyl.
 16. A chemical entity of claim1, wherein R² is methyl. 17-32. (canceled)
 33. A chemical entityselected from the group consisting of:Bicyclo[2.2.1]hept-2-yl-[4-((3R)-3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-aminedihydrochloride;N-Cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-propylpyridin-2-aminedihydrochloride;N-(Cyclopropylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amineditrifluoroacetate;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]pyridin-2-aminedihydrochloride;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[tetrahydrofuran-2-ylmethyl]pyridin-2-aminedihydrochloride;N-(4-Fluorobenzyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-aminedihydrochloride;N-Cyclopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-aminedihydrochloride;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;N-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(1-methylethyl)pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(1-methylethyl)pyridin-2-amine;4-[(3S)-3-Am inopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine;N-Cyclopentyl-4-piperazin-1-ylpyridin-2-amine;4-Piperazin-1-yl-N-propylpyridin-2-amine dihydrochloride;N-Benzyl-4-piperazin-1-ylpyridin-2-amine;N-(2-Methylpropyl)-4-piperazin-1-ylpyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine;4-(4-Methylpiperazin-1-yl)-N-(2-methylpropyl)pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-phenylpyridin-2-amine;4[3-(Methylamino)azetidin-1-yl]-N-(2-methylpropyl)pyridin-2-amine;N-(Cyclopropylmethyl)-4-piperazin-1-ylpyridin-2-amine;N-Butyl-4-piperazin-1-ylpyridin-2-amine;N-(2-Methoxyethyl)-4-piperazin-1-ylpyridin-2-amine;N-Phenyl-4-piperazin-1-ylpyridin-2-amine;4-Piperazin-1-yl-N-(tetrahydrofuran-2-ylmethyl)pyridin-2-amine;N-(4-Fluorobenzyl)-4-piperazin-1-ylpyridin-2-amine;N-(2,2-Dimethylpropyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(2-Methoxyethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine;Adamantan-2-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine;Adamantan-2-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;N-[(1R)-1-Cyclohexylethyl]-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;Adamantan-1-yl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;N-(Cyclohexylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(Cyclohexylmethyl)-4-(4-methylpiperazin-1-Opyridin-2-amine;N-[(1R)-1-Cyclohexylethyl]-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-[(1R)-1-Cyclohexylethyl]-4-(4-methylpiperazin-1-Opyridin-2-amine;Adamantan-2-yl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;3-{[4-(4-Methylpiperazin-1-yl)pyridin-2-yl]aminolpropan-1-ol;N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;Adamantan-1-yl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;Adamantan-1-yl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine;Adamantan-1-ylmethyl-[4-(3R)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-(4-methylpiperazin-1-yl)pyridin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine;4-(4-Methylpiperazin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine;N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(Cyclohexylmethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(Cyclopentylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(Cyclopentylmethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-Cyclopentyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;N-Bicyclo[2.2.1]hept-2-yl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-(4-Methylpiperazin-1-yl)-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;N-tert-Butyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;3-({4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-1-ol;N-Cyclopropyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(Cyclopentylmethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;N-Benzyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(2-Methoxyethyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;N-(2-Methoxyethyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;2-Methyl-1-({4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol;2-Methyl-1-{[4-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}propan-2-ol;2-Methyl-1-({4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-yl}amino)propan-2-ol;N-Butyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-(4-Methylpiperazin-1-yl)-N-(pyridin-2-ylmethyl)pyridin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine;N-(4-Fluorobenzyl)-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine;N-Cyclopentyl-4-(4-methylpiperazin-1-yl)pyridin-2-amine;N-(4-Fluorobenzyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;4-(4-Methylpiperazin-1-yl)-N-(2-phenylethyl)pyridin-2-amine;Adamantan-1-ylmethyl-[4-(3S)-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine;4-(4-Methylpiperazin-1-yl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyridin-2-amine; N-(Bicyclo[2.2.1]hept-2-ylmethyl)-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-butylpyridin-2-amine;Adamantan-1-ylmethyl-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine;N-(Cyclohexylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(2-methylpropyl)pyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine;N-Cyclopentyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-am ine; 4-Piperazin-1-yl-N-(pyridin-2-ylmethyl)pyridin-2-amine;N-(Cyclopentylmethyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;N-Cyclopentyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(4-fluorobenzyl)pyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyridin-2-amine;N-Bicyclo[2.2.1]hept-2-yl-4-(1,4-diazepan-1-yl)pyridin-2-amine;Adamantan-2-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-benzylpyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine;4-Piperazin-1-yl-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-bicyclo[2.2.1]hept-2-ylpyridin-2-amine;N-[(1R)-1-Cyclohexylethyl]-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;1-({4-[(3S)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclohexylpyridin-2-amine;N-(Cyclopentylmethyl)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine;4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(cyclopentylmethyl)pyridin-2-amine;1-({4-[(3R)-3-Aminopyrrolidin-1-yl]pyridin-2-yl}amino)-2-methylpropan-2-ol;N-tert-Butyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;N-Cyclopropyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;2-Methyl-1-({4-[3-(methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-2-ol;3-({4-[3-(Methylamino)azetidin-1-yl]pyridin-2-yl}amino)propan-1-ol;4-[3-(Methylamino)azetidin-1-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;N-Benzyl-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;N-(2-Methoxyethyl)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-N-[(1S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]pyridin-2-amine;N-tert-Butyl-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methoxyethyl)pyridin-2-amine;2-Methyl-1-[(4-piperazin-1-ylpyridin-2-yl)amino]propan-2-ol;N-{[(1S,2S,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-yl]methyl}-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-N-cyclopentylpyridin-2-amine;N-(2,2-Dimethylpropyl)-4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]pyridin-2-amine;4-[3-(Methylamino)azetidin-1-yl]-N-(2-phenylethyl)pyridin-2-amine;N-(4-FluorobenzyI)-4-[3-(methylamino)azetidin-1-yl]pyridin-2-amine;Adamantan-1-yl-[4-(3aR,6aR)-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyridin-2-yl]-amine;4-[3-(Methylamino)azetidin-1-yl]-N-(pyridin-2-ylmethyl)pyridin-2-amine;N-(Cyclopentylmethyl)-4-piperazin-1-ylpyridin-2-amine; andpharmaceutically acceptable salts thereof.
 34. (canceled)
 35. Apharmaceutical composition comprising an effective amount of at leastone chemical entity selected from the compounds of Formula (I)

wherein Z is CH; Y is CH; R¹ is: a) —(CH₂)₂OCH_(3,) —(CH₂)₂SCH_(3,) orC₁₋₈ alkyl, each independently unsubstituted or substituted with —OH or—CF₃; b) —(CH₂)₀₋₂-Ar¹, —CHR²-Ar¹, or —(CH₂)₀₋₂-Ar², each of said Ar¹and Ar² independently unsubstituted or substituted with halo, —CH_(3,)or —OCH_(,) Ar¹ is a 6-membered aromatic carbocyclic ring, Ar² is a 5 to6-membered heteroaromatic ring containing N, S or O; or c) cycloalkyl,—(CH2)-(monocyclic cycloalkyl), —(CH2)-(bridged polycyclic cycloalkyl),—(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH2)-(bridged monocyclic cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl, each of said cycloalkyl independentlyunsubstituted or substituted with one, two, or three C₁₋₄ alkylsubstituents; R² is —C₁₋₄ alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃ alkyl;provided that: when R¹ is isopropyl, then R^(c) is methyl; when R¹ is4-methylphenyl, then R^(c) is methyl; and pharmaceutically acceptablesalts of compounds of Formula (I).
 36. (canceled)
 37. (canceled)
 38. Apharmaceutical composition comprising and effective amount of at leastone chemical entity of claim
 33. 39. (canceled)
 40. A method of treatinga subject suffering from or diagnosed with a disease, disorder, ormedical condition mediated by histamine H₄ receptor activity, comprisingadministering to a subject in need of such treatment an effective amountof at least one chemical entity selected from compounds of Formula (I)

wherein Z is CH; Y is CH; R¹ is: a) —(CH₂)₂OCH_(3,) —(CH₂)₂SCH_(3,) orC₁₋₈ alkyl, each independently unsubstituted or substituted with —OH or—CF₃; b) —(CH₂)₀₋₂-Ar¹, —CHR²-Ar¹, or —(CH₂)₀₋₂-Ar², each of said Ar¹and Ar² independently unsubstituted or substituted with halo, —CH_(3,)or —OCH_(3,) Ar¹ is a 6-membered aromatic carbocyclic ring, Ar² is a 5to 6-membered heteroaromatic ring containing N, S or O; or c)cycloalkyl, —(CH₂)-(monocyclic cycloalkyl), —(CH₂)-(bridged polycycliccycloalkyl), —(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH₂)-(bridged monocyclic cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl, each of said cycloalkyl independentlyunsubstituted or substituted with one, two, or three C₁₋₄ alkylsubstituents; R² is —C₁₋₄ alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃ alkyl;provided that: when R¹ is isopropyl, then R^(c) is methyl; when R¹ is4-methylphenyl, then R^(c) is methyl; and pharmaceutically acceptablesalts of compounds of Formula (I).
 41. (canceled)
 42. (canceled)
 43. Amethod of treating a subject suffering from or diagnosed with a disease,disorder, or medical condition mediated by histamine H₄ receptoractivity, comprising administering to a subject in need of suchtreatment an effective amount of at least one chemical entity of claim33.
 44. (canceled)
 45. A method as in claim 40, wherein the disease,disorder or medical condition is inflammation.
 46. A method as in claim40, wherein the disease, disorder, or medical condition is selected fromthe group consisting of: inflammatory disorders, allergic disorders,dermatological disorders, autoimmune disease, lymphatic disorders, andimmunodeficiency disorders.
 47. A method as in claim 40, wherein thedisease, disorder, or medical condition is selected from: allergy,asthma, dry eye, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatorybowel diseases, colitis, Crohn's disease, ulcerative colitis, psoriasis,pruritus, itchy skin, atopic dermatitis, urticaria, hives, ocularinflammation, conjunctivitis, dry eye, nasal polyps, allergic rhinitis,nasal itch, scleroderma, autoimmune thyroid diseases, post-operativeadhesion, immune-mediated diabetes mellitus (type 1), type 2 diabetes,chronic renal failure, hepatic cholestasis, lupus, Myasthenia gravis,autoimmune neuropathies, Guillain-Barr, autoimmune uveitis, autoimmunehemolytic anemia, pernicious anemia, autoimmune thrombocytopenia,temporal arteritis, anti-phospholipid syndrome, vasculitides, Wegener'sgranulomatosis, Behcet's disease, dermatitis herpetiformis, pemphigusvulgaris, vitiligio, primary biliary cirrhosis, autoimmune hepatitis,autoimmune oophoritis, autoimmune orchitis, autoimmune disease of theadrenal gland, polymyositis, dermatomyositis, spondyloarthropathies,ankylosing spondylitis, Sjogren's syndrome, major depression disorder,bipolar disorder, treatment-resistant major depression disorder,treatment-resistant bipolar disorder, generalized anxiety disorder,social phobia, post traumatic stress disorder, and pain.
 48. A method asin claim 40, wherein the disease, disorder, or medical condition isselected from the group consisting of: allergy, asthma, rheumatoidarthritis, autoimmune diseases, and pruritus.
 49. A method formodulating histamine H₄ receptor activity, comprising exposing histamineH₄ receptor to an effective amount of at least one chemical entityselected from compounds of Formula (I)

wherein Z is CH; Y is CH; R¹ is: a) —(CH₂)₂OCH_(3,) —(CH₂)₂SCH_(3,) orC₁₋₈ alkyl, each independently unsubstituted or substituted with —OH or—CF₃; b) —(CH₂)₀₋₂-Ar¹, —CHR²-Ar¹, or —(CH₂)₀₋₂-Ar², each of said Ar¹and Ar² independently unsubstituted or substituted with halo, —CH_(3,)or —OCH_(3,) Ar¹ is a 6-membered aromatic carbocyclic ring, Ar² is a 5to 6-membered heteroaromatic ring containing N, S or O; or c)cycloalkyl, —(CH₂)-(monocyclic cycloalkyl), —(CH₂)-(bridged polycycliccycloalkyl), —(CHR²)-(monocyclic cycloalkyl), —(CH₂)-(fused cycloalkyl),—(CH₂)-(bridged monocyclic cycloalkyl), —(CH₂)₀₋₁-tetrahydrofuranyl, or—(CH₂)₀₋₁-tetrahydropyranyl, each of said cycloalkyl independentlyunsubstituted or substituted with one, two, or three C₁₋₄ alkylsubstituents; R² is —C₁₋₄ alkyl;

is

where R^(a), R^(b), and R^(c) are each independently H or C₁₋₃ alkyl;provided that: when R¹ is isopropyl, then R^(c) is methyl; when R¹ is4-methylphenyl, then R^(c) is methyl; and pharmaceutically acceptablesalts of compounds of Formula (I).
 50. (canceled)
 51. (canceled)
 52. Amethod for modulating histamine H₄ receptor activity, comprisingexposing histamine H₄ receptor to an effective amount of at least onechemical entity of claim
 33. 53. (canceled)
 54. A method as in claim 49,wherein said histamine H₄ receptor is in a human subject.
 55. A methodas in claim 54, wherein said human subject is suffering from or isdiagnosed with a disease, disorder, or medical condition mediated byhistamine H₄ receptor activity.
 56. A method as in claim 55, whereinsaid disease, disorder, or medical condition is allergy, rheumatoidarthritis, asthma, autoimmune diseases, or pruritus.
 57. A method as inclaim 40, wherein said administration comprises a topical application.58. A method as in claim 57, wherein said disorder or medical conditionis inflammation.
 59. A method as in claim 57, wherein said disorder ormedical condition is at least one of pruritus, urticaria and atopicdermatitis.